rs111033193

Positions:

chr7-107698111-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP7BS1_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The SLC26A4 p.Asn538Asn variant has been reported in the heterozygous state in one individual with unilateral hearing loss (PMID:20621367). However, this variant is synonymous and is not predicted by computational prediction analysis, using MaxEntScan, to impact splicing (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 60/24964) of the p.Asn538Asn variant in SLC26A4 is 0.19168% for African chromosomes in gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting; http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43517). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132671/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_region, synonymous

Scores

Splicing: ADA: 0.003720

Clinical Significance

Likely benign reviewed by expert panel U:2B:6

Conservation

PhyloP100: -0.972

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_benign. Variant got -3 ACMG points.

BP4

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

BP7

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

BS1

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.1614C>T	p.Asn538=	splice_region_variant, synonymous_variant	14/21	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.1614C>T	p.Asn538=	splice_region_variant, synonymous_variant	14/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000477350.5 linkuse as main transcript	n.461C>T		splice_region_variant, non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5 linkuse as main transcript	n.463C>T		splice_region_variant, non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.327C>T	p.Asn109=	splice_region_variant, synonymous_variant, NMD_transcript_variant	4/10			ENSP00000494344

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00213

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251058

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.000319

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:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000827

AC:

119

AN:

1439706

Hom.:

Cov.:

AF XY:

0.0000669

AC XY:

AN XY:

717756

show subpopulations

Gnomad4 AFR exome

AF:

0.00261

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000733

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000631

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000238

Hom.:

Bravo

AF:

0.000744

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	This variant is associated with the following publications: (PMID: 30245029, 20621367) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -

Pendred syndrome

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Likely benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jul 29, 2019	The SLC26A4 p.Asn538Asn variant has been reported in the heterozygous state in one individual with unilateral hearing loss (PMID: 20621367). However, this variant is synonymous and is not predicted by computational prediction analysis, using MaxEntScan, to impact splicing (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 60/24964) of the p.Asn538Asn variant in SLC26A4 is 0.19168% for African chromosomes in gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting; http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43517). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4, BP7. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.18

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0037

dbscSNV1_RF

Pathogenic

0.72

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