7-107674313-G-T

Position:

• chr7-107674313-G-T

Variant summary

Our verdict is Benign. Variant got -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
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 6.17

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• 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	c.565G>T	p.Ala189Ser	missense_variant	5/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.565G>T	p.Ala189Ser	missense_variant	5/21		NM_000441.2	ENSP00000494017	P1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152134 Hom.: 6 Cov.: 32

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

GnomAD3 exomes AF: 0.00105 AC: 264 AN: 251448 Hom.: 4 AF XY: 0.000625 AC XY: 85 AN XY: 135898

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 SAS 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.: 3 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727146

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000514

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: 0.00000630

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00347 AC: 528 AN: 152252 Hom.: 6 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74448

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000728 Hom.: 2

Bravo AF: 0.00406

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2019	This variant is associated with the following publications: (PMID: 25262649, 17309986, 27771369, 30245029, 30068397) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC26A4: BS1 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 14, 2011	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2016	- -

Pendred syndrome Benign:2

Benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 28, 2018	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). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Uncertain	0.64	D;D
Eigen	Benign	0.098
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	.;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.76

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

Other links and lift over

dbSNP: rs35045430; hg19: chr7-107314758;