VCV001676769.2 - ClinVar

NM_004604.5(STX4):c.232+6T>C

Germline

Classification

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.

(2)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004604.5(STX4):c.232+6T>C

Variation ID: 1676769 Accession: VCV001676769.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p11.2 16: 31034331 (GRCh38) [ NCBI UCSC ] 16: 31045652 (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	Oct 22, 2022	Mar 10, 2024	Mar 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004604.5:c.232+6T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001272095.1:c.-133T>C		5 prime UTR
NM_001272096.1:c.226+6T>C		intron variant
NC_000016.10:g.31034331T>C
NC_000016.9:g.31045652T>C

... more HGVS ... less HGVS

Protein change

Other names

NM_001272096.1:c.226+6T>C
NM_004604.4:c.232+6T>C
IVS3, T-C, +6

Canonical SPDI

NC_000016.10:31034330:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

OMIM: 186591.0002 VarSome

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
Gene	OMIM	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.
STX4		-	-	GRCh38 GRCh37	11	33

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.
Sensorineural hearing loss disorder	Likely pathogenic (1)	no assertion criteria provided	Apr 18, 2022	RCV002291511.2
Hearing loss, autosomal recessive 123	Pathogenic (1)	no assertion criteria provided	Mar 4, 2024	RCV003883471.1

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 (Apr 18, 2022)	no assertion criteria provided Method: research	Sensorineural hearing loss disorder (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Center for Statistical Genetics, Columbia University Accession: SCV002499562.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Publications: PubMed (1) PubMed: 30311386
Pathogenic (Mar 04, 2024)	no assertion criteria provided Method: literature only	DEAFNESS, AUTOSOMAL RECESSIVE 123 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV004698188.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 36355422 Comment on evidence: In 8 affected members from 2 sibships of a large consanguineous Pakistani family (pedigree 4768) segregating autosomal recessive nonsyndromic deafness (DFNB123; 620745), Schrauwen et al. … (more) In 8 affected members from 2 sibships of a large consanguineous Pakistani family (pedigree 4768) segregating autosomal recessive nonsyndromic deafness (DFNB123; 620745), Schrauwen et al. (2023) identified a splice site mutation in intron 3 of the STX4 gene (c.232+6T-C, NM_004604.5). Minigene assay, confirmed by Sanger sequencing, demonstrated skipping of exon 3, causing a frameshift predicted to result in a transcript targeted by nonsense-mediated decay. The unaffected parents and an unaffected sib were heterozygous for the mutation, which was present at low minor allele frequency (7.98 x 10(-6)) in the gnomAD-v2 database, but was not found in several other population databases, including TOPMed Bravo, Greater Middle East (GME), and gnomAD-v3. Zebrafish with morpholino-based knockdown of stx4 at the 5-prime donor site corresponding to the human c.232+6T-C variant showed loss of hearing and mechanotransduction function, along with severe morphologic defects. (less)

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

Title	Author	Journal	Year	Link
Syntaxin 4 is essential for hearing in human and zebrafish.	Schrauwen I	Human molecular genetics	2023	PMID: 36355422
Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.	Oza AM	Human mutation	2018	PMID: 30311386

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004604.5(STX4):c.232+6T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...