chr7-107683537-G-T

Position:

chr7-107683537-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.1001G>T(p.Gly334Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 8.64

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 7-107683537-G-T is Pathogenic according to our data. Variant chr7-107683537-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107683537-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1001G>T	p.Gly334Val	missense_variant, splice_region_variant	8/21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1001G>T	p.Gly334Val	missense_variant, splice_region_variant	8/21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

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:

0.00637

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250276

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460374

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726596

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74430

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2021	Variant summary: SLC26A4 c.1001G>T (p.Gly334Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site, with two of them also predicting that it creates a new cryptic exonic 5 donor site. Experimental evidence supports these predictions demonstrating the variant affects mRNA splicing leading to inclusion of intronic material and introduction of a premature stop codon (e.g. Walsh_2006, Wasano_2020). The variant allele was found at a frequency of 8e-06 in 250276 control chromosomes (gnomAD). c.1001G>T has been reported in the literature to segregate with disease in families with multiple homozygous individuals affected with Pendred Syndrome (e.g. Walsh_2006, Kahrizi_2009). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to impair ion transport activity (e.g. Dossena_2011, Wasano_2020). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 28, 2014	- -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	Severe to Profound SNHL -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	SLC26A4 c.1001G>T, p.G334V is a founder allele in the Palestinian population. Analysis of patient-derived RNA indicates that the variant disrupts the donor splice of SLC26A4 exon 8, with two mutant messages: (1) loss of exon 8 (83bp) with stop at codon 311. (2) activation of a cryptic splice donor with insertion of 40 bp in exon 8 message and stop at codon 355. (Abu Rayyan 2020). The variant is homozygous in 23 children from 10 Palestinian families with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 51/250276 alleles on gnomAD, all heterozygotes. -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -
Affects, no assertion criteria provided	in vitro;literature only	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 334 of the SLC26A4 protein (p.Gly334Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs146281367, gnomAD 0.003%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 16460646, 18813951, 28964290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189039). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 22116360). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the inclusion of part of intron 8 and introduces a premature termination codon (PMID: 16460646). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2024	Demonstrated to create a cryptic splice site and result in loss-of-function (PMID: 16460646); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31599023, 29372807, 16460646, 31033086, 28964290, 18813951, 27771369, 32747562, 31589614, 22116360, 34426522, 36555390, 35982127, 39107234, Stepanova2022(article), 34632506, 33614372, 26445815, 38474007) -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.9

D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.94

Loss of disorder (P = 0.0929);Loss of disorder (P = 0.0929);

MVP

0.99

MPC

0.075

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: 40

DS_DL_spliceai

0.46

Position offset: 0

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