This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (rs764082747, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076, 19499579). ClinVar contains an entry for this variant (Variation ID: 419887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006118.4(HAX1):c.91del (p.Glu31fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(12)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006118.4(HAX1):c.91del (p.Glu31fs)
Variation ID: 419887 Accession: VCV000419887.27
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 1q21.3 1: 154273373 (GRCh38) [ NCBI UCSC ] 1: 154245849 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Sep 16, 2024 May 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006118.4:c.91del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006109.2:p.Glu31fs frameshift NM_001018837.2:c.54-107del intron variant NM_006118.3:c.91delG NC_000001.11:g.154273373del NC_000001.10:g.154245849del NG_007369.1:g.5811del LRG_64:g.5811del LRG_64t1:c.91del LRG_64p1:p.Glu31fs - Protein change
- E31fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:154273372:G:
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00022
The Genome Aggregation Database (gnomAD) 0.00026
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HAX1 | - | - |
GRCh38 GRCh37 |
389 | 412 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2024 | RCV000485748.12 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000706106.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 20, 2023 | RCV003155204.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Dec 18, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450266.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002098330.1
First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
|
|
|
Pathogenic
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502270.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Kostmann syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024945.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Kostmann syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000835138.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (rs764082747, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076, 19499579). ClinVar contains an entry for this variant (Variation ID: 419887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568065.7
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19036076, 34426522, 31589614, 32054657, 19499579) (less)
|
|
|
Pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Kostmann syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002782074.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe congenital neutropenia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003845036.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00019 in 251294 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in HAX1 causing Severe Congenital Neutropenia (0.00019 vs 0.00079), allowing no conclusion about variant significance. c.91delG has been reported in the literature in individuals affected with Severe Congenital Neutropenia (e.g. Smith_2009, Carlsson_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Kostmann syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005085941.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with severe congenital neutropenia 3 (MIM#610738). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 58 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with neutropenia and classified as pathogenic in ClinVar (PMID: 37193639). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198426.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Mar 01, 2009)
|
no assertion criteria provided
Method: literature only
|
NEUTROPENIA, SEVERE CONGENITAL, 3, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025096.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 20, 2015 |
Comment on evidence:
In 2 unrelated Caucasian patients with autosomal recessive severe congenital neutropenia (SCN3; 610738), Smith et al. (2008) identified a homozygous 1-bp deletion (91delG) in exon … (more)
In 2 unrelated Caucasian patients with autosomal recessive severe congenital neutropenia (SCN3; 610738), Smith et al. (2008) identified a homozygous 1-bp deletion (91delG) in exon 2 of the HAX1 gene, resulting in a frameshift and premature termination. The first patient was a 19-year-old girl with a severe phenotype requiring G-CSF for many years in childhood. The second patient was a 16-year-old boy with a mild phenotype and only 1 or 2 infections per year. Neither patient had neurologic symptoms. The mutation was not detected in 131 healthy controls. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive severe congenital neutropenia type 3
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461732.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19036076, 34426522, 31589614, 32054657, 19499579)
Comment:
Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00019 in 251294 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in HAX1 causing Severe Congenital Neutropenia (0.00019 vs 0.00079), allowing no conclusion about variant significance. c.91delG has been reported in the literature in individuals affected with Severe Congenital Neutropenia (e.g. Smith_2009, Carlsson_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with severe congenital neutropenia 3 (MIM#610738). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 58 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with neutropenia and classified as pathogenic in ClinVar (PMID: 37193639). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (rs764082747, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076, 19499579). ClinVar contains an entry for this variant (Variation ID: 419887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19036076, 34426522, 31589614, 32054657, 19499579)
Comment:
Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00019 in 251294 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in HAX1 causing Severe Congenital Neutropenia (0.00019 vs 0.00079), allowing no conclusion about variant significance. c.91delG has been reported in the literature in individuals affected with Severe Congenital Neutropenia (e.g. Smith_2009, Carlsson_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with severe congenital neutropenia 3 (MIM#610738). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 58 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with neutropenia and classified as pathogenic in ClinVar (PMID: 37193639). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| HAX1-related congenital neutropenia: Long-term observation in paediatric and adult patients enrolled in the European branch of the Severe Chronic Neutropenia International Registry (SCNIR). | Pogozhykh D | British journal of haematology | 2023 | PMID: 37193639 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes. | Blombery P | Haematologica | 2021 | PMID: 32054657 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia. | Carlsson G | British journal of haematology | 2012 | PMID: 22624626 |
| Compound heterozygous HAX1 mutations in a Swedish patient with severe congenital neutropenia and no neurodevelopmental abnormalities. | Carlsson G | Pediatric blood & cancer | 2009 | PMID: 19499579 |
| Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds. | Smith BN | British journal of haematology | 2009 | PMID: 19036076 |
| HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). | Klein C | Nature genetics | 2007 | PMID: 17187068 |
Text-mined citations for rs764082747 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.