rs1554361015

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000441.2(SLC26A4):ā€‹c.1958T>Cā€‹(p.Val653Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.78
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 Likely_pathogenic. Variant got 8 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.1958T>C p.Val653Ala missense_variant 17/21 ENST00000644269.2 NP_000432.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.1958T>C p.Val653Ala missense_variant 17/21 NM_000441.2 ENSP00000494017 P1O43511-1
SLC26A4ENST00000492030.2 linkuse as main transcriptn.245T>C non_coding_transcript_exon_variant 2/65
SLC26A4ENST00000644846.1 linkuse as main transcriptc.671T>C p.Val224Ala missense_variant, NMD_transcript_variant 7/10 ENSP00000494344

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461768
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 11, 2024Variant summary: SLC26A4 c.1958T>C (p.Val653Ala) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1958T>C has been reported in the literature in the heterozygous state in individuals affected with nonsyndromic hearing loss (e.g. Scott_2000, Prasad_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Pendred syndrome. Experimental studies show that this variant results in lower levels of iodide and chloride transport and co-immunoprecipitates with EphA2 (e.g. Scott_2000, Li_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32165640, 14679580, 10861298). ClinVar contains an entry for this variant (Variation ID: 556316). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Pendred syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 28, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
2.0
M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.0
D;.
REVEL
Pathogenic
0.81
Sift
Benign
0.16
T;.
Sift4G
Benign
0.096
T;.
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.81
Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);
MVP
0.97
MPC
0.074
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.57
gMVP
0.73

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: rs1554361015; hg19: chr7-107342426; API