chr7-107689120-G-A

Position:

chr7-107689120-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. BA1PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), 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 Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132654/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:7

Conservation

PhyloP100: 7.13

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 -7 ACMG points.

PP3

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

BA1

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.1069G>A	p.Ala357Thr	missense_variant	9/21	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.1069G>A	p.Ala357Thr	missense_variant	9/21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000434

AC:

109

AN:

251198

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000167

AC:

244

AN:

1461614

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00454

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.00161

AC:

245

AN:

152234

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00532

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000368

Hom.:

Bravo

AF:

0.00187

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Feb 25, 2019	The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), 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 Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 02, 2016	p.Ala357Thr in exon 9 of SLC26A4: This variant is not expected to have clinical significance because it has been identified in 0.5% (53/10406) of African Americ an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs145467740). In addition, this variant was found in a patient w ith two pathogenic variants which sufficiently explained their hearing loss. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SLC26A4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.029

T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

0.99

D;D

Vest4

0.70

MVP

0.97

MPC

0.036

ClinPred

0.028

GERP RS

4.7

Varity_R

0.66

gMVP

0.94

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