rs111033193

Variant names:

• chr7-107698111-C-T
• rs111033193
• NM_000441.2:c.1614C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS1_Supporting BP4 BP7

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:2 B:6
• Conservation: PhyloP100: -0.972

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 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 rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1614C>T	p.Asn538Asn	splice_region_variant, synonymous_variant	Exon 14 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1614C>T	p.Asn538Asn	splice_region_variant, synonymous_variant	Exon 14 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000477350.5	n.461C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	4
SLC26A4	ENST00000480841.5	n.463C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 8	3
SLC26A4	ENST00000644846.1	n.324C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 10			ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152088 Hom.: 0 Cov.: 32

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: 54 AN: 251058 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135686

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.: 0 Cov.: 26 AF XY: 0.0000669 AC XY: 48 AN XY: 717756

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: 96 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74432

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.: 0

Bravo AF: 0.000744

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	This variant is associated with the following publications: (PMID: 30245029, 20621367) -
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	Oct 25, 2024	- -

Pendred syndrome Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -

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

Other links and lift over

dbSNP: rs111033193; hg19: chr7-107338556; COSMIC: COSV55914401; COSMIC: COSV55914401;