rs111033193

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1614C>T	p.Asn538Asn	splice_region synonymous	Exon 14 of 21	NP_000432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1614C>T	p.Asn538Asn	splice_region synonymous	Exon 14 of 21	ENSP00000494017.1
	SLC26A4	ENST00000477350.5	TSL:4	n.461C>T		splice_region non_coding_transcript_exon	Exon 4 of 5
	SLC26A4	ENST00000480841.5	TSL:3	n.463C>T		splice_region non_coding_transcript_exon	Exon 5 of 8

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

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251058 AF XY: 0.000147

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 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

African (AFR) AF: 0.00261 AC: 86 AN: 32990

American (AMR) AF: 0.000291 AC: 13 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000733 AC: 8 AN: 1091912

Other (OTH) AF: 0.000201 AC: 12 AN: 59642

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74432

African (AFR) AF: 0.00212 AC: 88 AN: 41502

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000744

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	2	Pendred syndrome (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.18
DANN	Benign	0.45
PhyloP100		-0.97
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

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