Variant rs111033407 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1342-2_1343dup variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000134 in 1,608,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.30

Variant links:

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-107694617-G-GCAGT is Pathogenic according to our data. Variant chr7-107694617-G-GCAGT is described in ClinVar as [Pathogenic]. Clinvar id is 43506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1342-2_1343dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1342-2_1343dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000441.2	ENSP00000494017	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251046

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1456246

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

724902

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000642

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2023	Frameshift variant predicted to result in protein truncation or nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease; In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 19204907, 21704276, 31589614, 15689455) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change falls in intron 11 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. This variant is present in population databases (rs756270039, gnomAD 0.009%). This variant has been observed in individuals with deafness with enlargement of the vestibular aqueduct (PMID: 15689455, 19204907). This variant is also known as c.1342-2_1343dup (p.Leu450Glyfs*19) if splicing occurs at the native splice site. It is also referred to as c.1340_1343dup and 1343‚Äì1344insAGTC in the literature. ClinVar contains an entry for this variant (Variation ID: 43506). For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 23, 2020

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 27, 2012

The 1342-2_1343dupAGTC variant in SLC26A4 has been reported as a compound hetero zygous variant in 3 individuals with enlarged vestibular aqueducts (EVA) and has been identified by our laboratory in 3 other individuals each of whom has a sec ond pathogenic SLC26A4 variant (Choi 2009, LMM unpublished data). This variant l eads to the duplication of a conserved splice site at the beginning of exon 12, which could either deleteriously affect splicing of the transcript or cause a fr ameshift if 4 additional bases are included in the exon. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). -

SLC26A4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2023

The SLC26A4 c.1342-2_1343dupAGTC variant is predicted to result in a duplication affecting a canonical splice site. This variant has been reported along with a second SLC26A4 variant in individuals with an enlarged vestibular aqueduct (described as 1343-1344insAGTC in Pryor et al. 2005. PubMed ID: 15689455; described as c.1340_1343dup in Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107335062-G-GCAGT). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over