rs539699299

Positions:

• chr7-107661725-C-A
• chr7-107661725-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.84C>A​(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,558,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.699

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:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107661725-C-A is Pathogenic according to our data. Variant chr7-107661725-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.84C>A	p.Ser28Arg	missense_variant	2/21	ENST00000644269.2	NP_000432.1
SLC26A4-AS1	NR_028137.1	n.74G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.84C>A	p.Ser28Arg	missense_variant	2/21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1406212 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 695208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 12, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 02, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 07, 2024	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2017	The c.84C>A variant (rs539699299) has been observed as a homozygote (Park 2003) or in trans with a pathogenic variant (Ladsous 2014) in patients with a clinical diagnosis of Pendred syndrome (PS). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 1 out of 30,956 chromosomes). Additionally, a different nucleic acid change leading to the same amino acid substitution (c.82A>C; p.Ser28Arg) a different variant in same codon (c.82A>G; p.Ser28Gly) have also been identified in patients with enlarged vestibular aqueduct (EVA; Park 2005 and Okamoto 2014, respectively). Analysis of the p.Ser28Arg variant in heterologous cell culture has revealed this substitution results in defects in ion flux compared to wild-type SLC26A4 protein (Dossena 2006a, Dossena 2006b, Yoon 2008). This variant is also listed in the ClinVar database as likely pathogenic (Variation ID: 188998). Therefore, the c.84C>A variant satisfies our criteria for classification as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the SLC26A4 protein (p.Ser28Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11919333, 15679828, 16570074, 24224479, 29739340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188998). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 16791000, 18310264). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.027	D;.;D
Polyphen		0.92	P;P;.
Vest4		0.91
MutPred		0.75		Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);
MVP		0.96
MPC		0.020
ClinPred		0.93	D
GERP RS		2.4
Varity_R		0.65
gMVP		0.76

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: rs539699299; hg19: chr7-107302170;