ClinVar Genomic variation as it relates to human health
NM_199242.3(UNC13D):c.2448-13G>A
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.
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(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_199242.3(UNC13D):c.2448-13G>A
Variation ID: 1518480 Accession: VCV001518480.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.1 17: 75831361 (GRCh38) [ NCBI UCSC ] 17: 73827442 (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 Mar 28, 2022 Apr 6, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_199242.3:c.2448-13G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000017.11:g.75831361C>T NC_000017.10:g.73827442C>T NG_007266.1:g.18357G>A LRG_122:g.18357G>A LRG_122t1:c.2448-13G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000017.11:75831360:C:T
-
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) 0.00001
- 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. |
|||
UNC13D | - | - |
GRCh38 GRCh37 |
1395 | 1565 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 25, 2024 | RCV002021777.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2022 | RCV002469449.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766557.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: UNC13D c.2448-13G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: UNC13D c.2448-13G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 3' acceptor site, while three predict the variant creates a novel 3' acceptor site, 11 nucleotides upstream from the original splice-site. These predictions were confirmed by a publication reporting experimental evidence demonstrating that the new acceptor splice site created by the variant was exclusively used in the splicing process, with no traces of residual usage of the wild type splice-site (Alsina_2014), as a consequence, this would result in a frameshift and a premature stop codon at the protein level. The variant allele was found at a frequency of 4.2e-06 in 239744 control chromosomes (gnomAD). c.2448-13G>A has been reported in the literature in a homozygous- and in multiple compound heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Alsina_2014, Zhang_2019, Liao_2020, Shabrish_2021). Most of these reports also demonstrated severely decreased NK cell cytotoxic activity in patient derived cells, in addition, the Munc13-4 protein (coded for by the UNC13D gene) was undetectable on western blot in the sample derived from a homozygous patient (Liao_2020). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 3
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002308850.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 25 of the UNC13D gene. It does not directly change the encoded amino acid sequence of the UNC13D protein. … (more)
This sequence change falls in intron 25 of the UNC13D gene. It does not directly change the encoded amino acid sequence of the UNC13D protein. This variant is present in population databases (rs753762300, gnomAD no frequency). This variant has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 24825797, 29262924, 31388699, 32327331, 33746956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS25-13G>A. ClinVar contains an entry for this variant (Variation ID: 1518480). 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)
|
|
Uncertain significance
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 3
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806298.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Growth and Development Research Center, Tehran University of Medical Sciences
Accession: SCV002586259.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Number of individuals with the variant: 2
Age: 1-15 months
Sex: mixed
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India. | Shabrish S | Frontiers in immunology | 2021 | PMID: 33746956 |
UNC13D mutation presenting as fulminant familial hemophagocytic lymphohistiocytosis. | Liao CH | Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi | 2020 | PMID: 32327331 |
Genetic characterization of pediatric primary hemophagocytic lymphohistiocytosis in China: a single-center study. | Zhang L | Annals of hematology | 2019 | PMID: 31388699 |
[Familial Haemophagocytic Lymphohistiocytosis Occurs in A Fetus at His Third Trimester-A Case Report]. | Huang JB | Zhongguo shi yan xue ye xue za zhi | 2017 | PMID: 29262924 |
Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection. | Alsina L | Clinical immunology (Orlando, Fla.) | 2014 | PMID: 24825797 |
Text-mined citations for rs753762300 ...
HelpRecord last updated Apr 06, 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.