rs55638457

Variant summary

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

The NM_000441.2(SLC26A4):ā€‹c.1790T>Cā€‹(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: š‘“ 0.0062 ( 7 hom., cov: 32)
Exomes š‘“: 0.0086 ( 118 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

4
9
5

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]

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
SLC26A4NM_000441.2 linkc.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 Appris UniProt
SLC26A4ENST00000644269.2 linkc.1790T>C p.Leu597Ser missense_variant Exon 16 of 21 NM_000441.2 ENSP00000494017.1 O43511-1
SLC26A4ENST00000480841.5 linkn.639T>C non_coding_transcript_exon_variant Exon 7 of 8 3
SLC26A4ENST00000644846.1 linkn.500T>C non_coding_transcript_exon_variant Exon 6 of 10 ENSP00000494344.1 A0A2R8Y4W7
SLC26A4ENST00000492030.2 linkn.91-644T>C intron_variant Intron 1 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.00624
AC:
949
AN:
152186
Hom.:
7
Cov.:
32
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.:
28
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.:
27
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.:
7
Cov.:
32
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.:
7
Bravo
AF:
0.00601
TwinsUK
AF:
0.00863
AC:
32
ALSPAC
AF:
0.00960
AC:
37
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00907
AC:
78
ExAC
AF:
0.00823
AC:
999
Asia WGS
AF:
0.00664
AC:
23
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
Oct 28, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 10, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 04, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:5
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 15, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 28, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC26A4: BS1, BS2 -

Pendred syndrome Benign:4
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 05, 2021
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 07, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 18, 2021
Pars Genome Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1Benign:1
Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Sep 05, 2021
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Benign:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.80
.;T
MetaRNN
Benign
0.0087
T;T
MetaSVM
Uncertain
0.78
D
MutationAssessor
Benign
2.0
M;M
PrimateAI
Uncertain
0.60
T
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
T
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.

Other links and lift over

dbSNP: rs55638457; hg19: chr7-107341628; API