chr7-107661725-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.699

Variant links:

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 links:

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

SLC26A4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.84C>A	p.Ser28Arg	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.74G>T		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 link	c.84C>A	p.Ser28Arg	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

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:

AN:

1406212

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

695208

show subpopulations

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:

AN:

152374

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74510

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:3

Feb 12, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:3

Jan 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Sep 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a second SLC26A4 variant in additional patients with Pendred syndrome or hearing loss with enlarged vestibular aqueduct in published literature (PMID: 16570074, 24224479); Published functional studies demonstrate a damaging effect on chloride transport and protein glycosylation (PMID: 16791000, 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: 16914891, 31980526, 30275481, 22285650, 24341454, 19040761, 33199029, 19017801, 28941661, 27610647, 38802577, 16950989, 18310264, 24224479, 16791000, 12676893, 11919333, 16570074, 26361564, 29739340) -

May 19, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 16791000, 18310264). 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. ClinVar contains an entry for this variant (Variation ID: 188998). 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. 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 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). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Jan 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

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

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Uncertain

0.68

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over