NM_001008537.3(NEXMIF):c.3458dup (p.Asn1153fs) AND X-linked intellectual disability, Cantagrel type

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001809825.4

Allele description [Variation Report for NM_001008537.3(NEXMIF):c.3458dup (p.Asn1153fs)]

NM_001008537.3(NEXMIF):c.3458dup (p.Asn1153fs)

Gene:

NEXMIF:neurite extension and migration factor [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xq13.3

Genomic location:

Preferred name:

NM_001008537.3(NEXMIF):c.3458dup (p.Asn1153fs)

HGVS:

NC_000023.11:g.74741105dup
NG_027726.1:g.189354dup
NM_001008537.3:c.3458dupMANE SELECT
NP_001008537.1:p.Asn1153fs
NC_000023.10:g.73960933_73960934insT
NC_000023.10:g.73960940dup
NM_001008537.1:c.3458dup
NM_001008537.2:c.3458dupA

Protein change:

N1153fs

Links:

dbSNP: rs1602211123

NCBI 1000 Genomes Browser:

rs1602211123

Molecular consequence:

NM_001008537.3:c.3458dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: X-linked intellectual disability, Cantagrel type (XLID98)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 98
Identifiers:: MONDO: MONDO:0010483; MedGen: C3806730; Orphanet: 85277; OMIM: 300912

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002059025	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004100629	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801623	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Aug 29, 2018)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002059025

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004100629

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004801623

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Aug 29, 2018)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From 3billion, SCV002059025.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported to be associated with NEXMIF related disorder (ClinVar ID: VCV000653605). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004100629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The frameshift duplication p.N1153Kfs*8 in NEXMIF (NM_001008537.3) has been reported previously in affected individuals (Stamberger H et al,2021). It has been submitted previously to ClinVar as Pathogenic. The p.N1153Kfs*8 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004801623.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The KIAA2022 c.3458dupA p.(Asn1153LysfsTer8) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence the c.3458dupA p.(Asn1153LysfsTer8) variant is classified as pathogenic for X-linked intellectual developmental disorder.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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