rs17154335

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000441.2(SLC26A4):c.1826T>G(p.Val609Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00773 in 1,610,138 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V609V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 429 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 371 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.74

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016256273).

BP6

Variant 7-107701849-T-G is Benign according to our data. Variant chr7-107701849-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 43526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107701849-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1826T>G	p.Val609Gly	missense_variant	17/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1826T>G	p.Val609Gly	missense_variant	17/21		NM_000441.2	P1	O43511-1
SLC26A4	ENST00000480841.5 linkuse as main transcript	n.675T>G		non_coding_transcript_exon_variant	8/8	3
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.113T>G		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.539T>G	p.Val180Gly	missense_variant, NMD_transcript_variant	7/10

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6155

AN:

152208

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0107

AC:

2695

AN:

250926

Hom.:

171

AF XY:

0.00794

AC XY:

1076

AN XY:

135582

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00430

AC:

6268

AN:

1457812

Hom.:

371

Cov.:

AF XY:

0.00374

AC XY:

2712

AN XY:

725596

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.00798

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000396

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0406

AC:

6180

AN:

152326

Hom.:

429

Cov.:

AF XY:

0.0388

AC XY:

2894

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.00845

Hom.:

161

Bravo

AF:

0.0458

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.143

AC:

629

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0132

AC:

1596

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 20981092, 27884173, 29739340, 22116359, 15689455, 19017801, 22389666, 25262649, 23273637, 30245029, 26886089, 23280318, 19204907, 30068397, 31656273) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Pendred syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.036

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

-1.1

N;N

MutationTaster

Benign

0.20

P;P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

2.2

N;.

REVEL

Benign

0.27

Sift

Benign

0.55

T;.

Sift4G

Benign

0.39

T;.

Polyphen

0.0

B;B

Vest4

0.038

MPC

0.011

ClinPred

0.0099

GERP RS

5.8

Varity_R

0.093

gMVP

0.57

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