rs111033191
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000441.2(SLC26A4):c.1592A>C(p.Lys531Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SLC26A4
NM_000441.2 missense
NM_000441.2 missense
Scores
2
13
3
Clinical Significance
Conservation
PhyloP100: 2.46
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000441.2
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1592A>C | p.Lys531Thr | missense_variant | 14/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1592A>C | p.Lys531Thr | missense_variant | 14/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000477350.5 | n.439A>C | non_coding_transcript_exon_variant | 4/5 | 4 | ||||
SLC26A4 | ENST00000480841.5 | n.441A>C | non_coding_transcript_exon_variant | 5/8 | 3 | ||||
SLC26A4 | ENST00000644846.1 | c.305A>C | p.Lys102Thr | missense_variant, NMD_transcript_variant | 4/10 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 08, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys531Thr variant in SLC26A4 has been previously reported by our laboratory in one indivi dual with hearing loss and EVA, who also has another reported pathogenic variant in SLC26A4 in trans. This variant has not been identified in large population s tudies. Computational prediction tools and conservation analyses suggest that th e p.Lys531Thr variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. However, the presence of this variant in trans with a reported pathogenic variant in SLC26A4 in an individual with he aring loss and EVA, the extremely low allele frequency in the general population , and computational predictions increase the likelihood that the p.Lys531Thr var iant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Lys531Thr variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
P;P
Vest4
MutPred
Loss of ubiquitination at K531 (P = 0.0134);Loss of ubiquitination at K531 (P = 0.0134);
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