chr7-107701986-A-G

Position:

chr7-107701986-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PM3PP1PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID:26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID:26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 8/22/2023 (PM2_Supporting, PP4, PM3, PP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA261421/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:3

Conservation

PhyloP100: 3.78

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 Likely_pathogenic. Variant got 5 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1963A>G	p.Ile655Val	missense_variant	17/21	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.1963A>G	p.Ile655Val	missense_variant	17/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.250A>G		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.676A>G	p.Ile226Val	missense_variant, NMD_transcript_variant	7/10			ENSP00000494344

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251192

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 655 of the SLC26A4 protein (p.Ile655Val). This variant is present in population databases (rs397516424, gnomAD 0.006%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 26894580, 36703223). ClinVar contains an entry for this variant (Variation ID: 43528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SLC26A4: PM3:Strong, PM2, PP4, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26894580, 36703223, 37811145) -

Pendred syndrome

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Aug 27, 2023	The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID: 26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID: 26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 8/22/2023 (PM2_Supporting, PP4, PM3, PP1) -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 05, 2024

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM2, PM1, PM3, PP1 -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PM3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.081

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.89

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.70

N;.

REVEL

Benign

0.24

Sift

Benign

0.48

T;.

Sift4G

Benign

0.27

T;.

Polyphen

0.025

B;B

Vest4

0.23

MVP

0.87

MPC

0.012

ClinPred

0.085

GERP RS

5.7

Varity_R

0.15

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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