rs111033423

Positions:

• chr7-107661658-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. 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. 13/20 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

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

Verdict is Benign. Variant got -13 ACMG points.

• 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 Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=5, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.17G>T	p.Gly6Val	missense_variant	2/21		NM_000441.2	ENSP00000494017	P1
SLC26A4-AS1	ENST00000668981.1	n.201C>A		non_coding_transcript_exon_variant	1/2

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

GnomAD3 exomes AF: 0.00248 AC: 440 AN: 177348 Hom.: 6 AF XY: 0.00312 AC XY: 303 AN XY: 97130

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 SAS exome AF: 0.0158

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000256

Gnomad4 ASJ exome AF: 0.00259

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000685

Gnomad4 OTH exome AF: 0.00181

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

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0242

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000425 Hom.: 0

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

Likely benign, criteria provided, single submitter	literature only	Counsyl	Oct 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2019	This variant is associated with the following publications: (PMID: 28444304, 20597900, 25991456, 26188157, 20601923) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 23, 2018	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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2017	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). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	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;.
MutationTaster	Benign	1.0	N
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

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: rs111033423; hg19: chr7-107302103;