rs111033318

Positions:

• chr7-107702050-T-A
• chr7-107702050-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.2027T>A​(p.Leu676Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,453,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.78

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-107702050-T-A is Pathogenic according to our data. Variant chr7-107702050-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107702050-T-A is described in Lovd as [Pathogenic]. Variant chr7-107702050-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2027T>A	p.Leu676Gln	missense_variant	17/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2027T>A	p.Leu676Gln	missense_variant	17/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.314T>A		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1	n.737T>A		non_coding_transcript_exon_variant	7/10			ENSP00000494344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453434 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 723772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 11, 2014	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 15, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2024	Published functional studies demonstrate defective transported activity and intracellular retention (PMID: 14715652, 18310264); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21154317, 36107570, 35853923, 34943614, 14715652, 18310264, 12676893, 21961810, 25015771, 32868181, 32645618, 33724713, 34170635, 35982127, 36833263, 25266519, 34426522, 32877901, 31541171, 30896630, 30275481) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 676 of the SLC26A4 protein (p.Leu676Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 12676893, 14715652, 21961810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 14715652, 18310264). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Rare genetic deafness Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2007

- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PS3_Supporting+PM3_VeryStrong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	.;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.95		Loss of stability (P = 0.0243);Loss of stability (P = 0.0243);
MVP		0.99
MPC		0.074
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111033318; hg19: chr7-107342495; COSMIC: COSV99072589; COSMIC: COSV99072589;