rs55638457

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000441.2(SLC26A4):c.1790T>C(p.Leu597Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00837 in 1,598,500 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 118 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 6.17

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 Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.008705229).

BP6

Variant 7-107701183-T-C is Benign according to our data. Variant chr7-107701183-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43525.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=7}. Variant chr7-107701183-T-C is described in Lovd as [Benign]. Variant chr7-107701183-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00623 (949/152304) while in subpopulation SAS AF= 0.0282 (136/4820). AF 95% confidence interval is 0.0244. There are 7 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.1790T>C	p.Leu597Ser	missense_variant	Exon 16 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 link	c.1790T>C	p.Leu597Ser	missense_variant	Exon 16 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000480841.5 link	n.639T>C		non_coding_transcript_exon_variant	Exon 7 of 8	3
SLC26A4	ENST00000644846.1 link	n.500T>C		non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000492030.2 link	n.91-644T>C		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

949

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00833

AC:

2092

AN:

251102

Hom.:

AF XY:

0.00982

AC XY:

1333

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0281

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00756

Gnomad OTH exome

AF:

0.00752

GnomAD4 exome

AF:

0.00860

AC:

12437

AN:

1446196

Hom.:

118

Cov.:

AF XY:

0.00942

AC XY:

6786

AN XY:

720586

show subpopulations

Gnomad4 AFR exome

AF:

0.00127

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.0204

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0294

Gnomad4 FIN exome

AF:

0.000843

Gnomad4 NFE exome

AF:

0.00782

Gnomad4 OTH exome

AF:

0.00826

GnomAD4 genome

AF:

0.00623

AC:

949

AN:

152304

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00686

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0282

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00813

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00856

Hom.:

Bravo

AF:

0.00601

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00823

AC:

999

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00856

EpiControl

AF:

0.00794

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 24, 2014	p.Leu597Ser in exon 16 of SLC26A4: Although this variant has been reported in pa tients with Pendred syndrome and nonsyndromic hearing loss with enlarged vestibu lar aqueducts (EVA) (Campbell et al 2001, Fugazzola et al 2002, Blons 2004, Pryo r 2005), it has also been found in 2.7% (449/16590) of South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55638457). In addition, this variant has been identified by our laboratory in many individuals, none of whom had a pathogenic variant on the second allele. I n summary, this data meets our criteria to classify this variant as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC26A4: BS1, BS2 -

Pendred syndrome

Benign:4

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0087

T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.4

D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.072

T;.

Polyphen

1.0

D;D

Vest4

0.75

MVP

0.99

MPC

0.074

ClinPred

0.013

GERP RS

5.7

Varity_R

0.66

gMVP

0.71

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