rs786204739
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000441.2(SLC26A4):c.1586T>C(p.Ile529Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I529S) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SLC26A4
NM_000441.2 missense
NM_000441.2 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 7.15
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 Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000441.2
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr7-107698083-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
?
Variant 7-107698083-T-C is Pathogenic according to our data. Variant chr7-107698083-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1687453.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1586T>C | p.Ile529Thr | missense_variant | 14/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1586T>C | p.Ile529Thr | missense_variant | 14/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000477350.5 | n.433T>C | non_coding_transcript_exon_variant | 4/5 | 4 | ||||
SLC26A4 | ENST00000480841.5 | n.435T>C | non_coding_transcript_exon_variant | 5/8 | 3 | ||||
SLC26A4 | ENST00000644846.1 | c.299T>C | p.Ile100Thr | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000189160, PMID:17718863). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.815>=0.6, 3CNET: 0.902>=0.75). A missense variant is a common mechanism associated with Deafness, autosomal recessive 4. It is absent from the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
P;P
Vest4
MutPred
Loss of stability (P = 0.0062);Loss of stability (P = 0.0062);
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