7-107661658-G-T

Variant names:

• chr7-107661658-G-T
• rs111033423
• NM_000441.2:c.17G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000441.2(SLC26A4):​c.17G>T​(p.Gly6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,567,808 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00086 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.233
• Publications: 9 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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025506318).
• BP6: Variant 7-107661658-G-T is Benign according to our data. Variant chr7-107661658-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43524.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00086 (131/152386) while in subpopulation SAS AF = 0.0242 (117/4834). AF 95% confidence interval is 0.0206. There are 4 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.17G>T	p.Gly6Val	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1
SLC26A4-AS1	NR_028137.1	n.141C>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.17G>T	p.Gly6Val	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.000860 AC: 131 AN: 152268 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00248 AC: 440 AN: 177348 AF XY: 0.00312

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.0000768

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00113 AC: 1597 AN: 1415422 Hom.: 30 Cov.: 30 AF XY: 0.00155 AC XY: 1089 AN XY: 701032

African (AFR) AF: 0.00 AC: 0 AN: 32746

American (AMR) AF: 0.0000256 AC: 1 AN: 39014

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 66 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 37816

South Asian (SAS) AF: 0.0166 AC: 1347 AN: 81316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40158

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5574

European-Non Finnish (NFE) AF: 0.0000685 AC: 75 AN: 1094342

Other (OTH) AF: 0.00181 AC: 107 AN: 58976

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152386 Hom.: 4 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74524

African (AFR) AF: 0.0000721 AC: 3 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0242 AC: 117 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000492 Hom.: 3

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000127 AC: 1

ExAC AF: 0.00227 AC: 263

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Benign:4

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nov 11, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:3

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28444304, 20597900, 25991456, 26188157, 20601923) -

Jan 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17G>T; p.Gly6Val variant (rs111033423, ClinVar variant ID 43524) has been reported in patients with hearing loss (Pourova 2010, Tang 2015) and congenital hypothyroidism (de Filippis 2017); however, it was also detected at a similar frequency in a control population (Pourova 2010). This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 1.6% (identified on 398 out of 25,068 chromosomes, including 6 homozygotes). The glycine at position 6 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Gly6Val variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the p.Gly6Val variant is likely to be benign. -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly6Val variant in exon 2 of SLC26A4: This variant is not expected to have clinical significance because it has been identified in 1.6% (398/25068) of Sou th Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs111033423). -

Jul 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC26A4 c.17G>T (p.Gly6Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 177348 control chromosomes, predominantly at a frequency of 0.016 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=2) and benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	.;T;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		0.23
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.35	T;.;T
Sift4G	Benign	0.35	T;.;T
Polyphen		0.0050	B;B;.
Vest4		0.15
MVP		0.61
MPC		0.012
ClinPred		0.0063	T
GERP RS		0.15
Varity_R		0.061
gMVP		0.42
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs111033423; hg19: chr7-107302103;