NM_000441.2:c.565G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ala1898Ser variant in the SLC26A4 gene is 1.2% (324/24040) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132732/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.0035 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 6.17

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Pendred syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.565G>T	p.Ala189Ser	missense_variant	Exon 5 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.565G>T	p.Ala189Ser	missense_variant	Exon 5 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

528

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.0000147

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00105

AC:

264

AN:

251448

AF XY:

0.000625

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000330

AC:

482

AN:

1461622

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0124

AC:

416

AN:

33466

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111782

Other (OTH)

AF:

0.000563

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00347

AC:

528

AN:

152252

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0122

AC:

506

AN:

41546

American (AMR)

AF:

0.000850

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00406

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC26A4: BS1 -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25262649, 17309986, 27771369, 30245029, 30068397) -

not specified

Benign:2

Nov 14, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala189Ser in exon 5 of SLC26A4: This variant is not expected to have clinical si gnificance because it has been identified in 0.38% (25/6628) of chromosomes from a broad population (dbSNP rs35045430). -

May 05, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pendred syndrome

Benign:2

Jan 02, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 28, 2018

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the p.Ala1898Ser variant in the SLC26A4 gene is 1.2% (324/24040) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.64

D;D

Eigen

Benign

0.098

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

1.3

L;L

PhyloP100

6.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.48

Sift

Benign

0.13

T;.

Sift4G

Benign

0.16

T;.

Polyphen

0.30

B;B

Vest4

0.42

MVP

0.97

MPC

0.012

ClinPred

0.018

GERP RS

5.1

Varity_R

0.20

gMVP

0.76

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over