rs1554361015
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000441.2(SLC26A4):āc.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
NM_000441.2 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 6.78
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]
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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 |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1958T>C | p.Val653Ala | missense_variant | 17/21 | NM_000441.2 | ENSP00000494017 | P1 | ||
SLC26A4 | ENST00000492030.2 | n.245T>C | non_coding_transcript_exon_variant | 2/6 | 5 | |||||
SLC26A4 | ENST00000644846.1 | c.671T>C | p.Val224Ala | missense_variant, NMD_transcript_variant | 7/10 | ENSP00000494344 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727190
GnomAD4 exome
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1
AN:
1461768
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31
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1
AN XY:
727190
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
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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 submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2024 | Variant 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 submitter | clinical testing | Counsyl | Jan 28, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
D;D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at