rs199588131

Positions:

chr7-107702006-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000441.2(SLC26A4):c.1983C>A(p.Asp661Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:1

Conservation

PhyloP100: -0.378

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1983C>A	p.Asp661Glu	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 linkuse as main transcript	c.1983C>A	p.Asp661Glu	missense_variant	17/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.270C>A		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.696C>A	p.Asp232Glu	missense_variant, NMD_transcript_variant	7/10			ENSP00000494344

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251204

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00174

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00111

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000830

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	May 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000441.1(SLC26A4):c.1983C>A(D661E) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. D661E has been observed in cases with relevant disease (PMID: 25761933, 23185506, 23638949). Functional assessments of this variant are not available in the literature. D661E has been observed in population frequency databases (gnomAD: EAS 0.16%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.1983C>A(D661E) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2022	Variant summary: SLC26A4 c.1983C>A (p.Asp661Glu) results in a conservative amino acid change located in the STAS (Sulphate Transporter and AntiSigma factor antagonist) domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0017 in the gnomAD database. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0035), allowing no conclusion about variant significance. The variant, c.1983C>A, has been reported in the literature in multiple heterozygous individuals who were affected with hearing loss (e.g. Schrijver_2006, Yuan_2012, Dahl_2013, Gu_2014, Iwasa_2019) or congenital hypothyroidism with normal hearing (e.g. Fu_2016, Zhang_2021), however, in some of these hearing loss cases co-occurrences with other (potentially) pathogenic biallelic variants in other genes have been reported, which could explain the phenotype (e.g. in the GJB2 gene, in Schrijver_2006 and Dahl_2013; and in the OTOF gene in Iwasa_2019), providing supporting evidence for a benign role. In addition, in a family, the proband who was affected with hearing loss, had two pathogenic SLC26A4 variants in compound heterozygous state, but didn't carry the variant, while the unaffected mother and unaffected sister both carried the c.1983C>A variant in trans with a pathogenic SLC26A4 variant (Yu_2019). On the other hand, a recent publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the p.Asp661Glu variant affected the ion transport function of the protein, but had no effect on the membrane location (Zhang_2021). Furthermore, the Deafness Variation Database (DVD), classified the variant as pathogenic, citing overlapping evidence utilized in the context of this evaluation (Azaiez_2018). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) VUS (n=6), and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 23, 2010	Variant classified as Uncertain Significance - Favor Benign. The Asp661Glu varia nt in SLC26A4 has been observed in one Asian individual with hearing loss and re tinal disease. This individual did not have a variant on the second copy of the SLC26A4 gene. Computational analyses (biochemical amino acid properties, homolog y, PolyPhen, SIFT, AlignGVGD) do not provide strong support for or against patho genicity. In summary, the clinical significance of this variant cannot be determ ined at this time; however, given the lack of association between SLC26A4 varian ts and retinal disease, the variant is more likley benign. -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:2

Uncertain significance, 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 27, 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 provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2020	Observed heterozygous with no second SLC26A4 variant in multiple unrelated patients (Yuan et al., 2012; Huang et al., 2018; Fu et al., 2016; Yao et al., 2013); Observed in a patient with hearing loss in published literature who harbored a homozygous variant in the OTOA gene (Iwasa et al., 2019); Observed in trans with a pathogenic variant in the unaffected parent of a patient with hearing loss in published literature; the affected child harbored two SLC26A4 variants and did not inherit D661E (Yu et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29605365, 21704276, 31095577, 30086623, 23638949, 26886089, 18274916, 16952406, 25761933, 30245029, 23185506, 30762455) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;D

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

0.72

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0030

D;.

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.90

Loss of sheet (P = 0.3635);Loss of sheet (P = 0.3635);

MVP

0.86

MPC

0.076

ClinPred

0.32

GERP RS

-11

Varity_R

0.89

gMVP

0.91

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