rs766206507
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000441.2(SLC26A4):āc.1673A>Gā(p.Asn558Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,439,224 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N558I) has been classified as Pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1673A>G | p.Asn558Ser | missense_variant | 15/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1673A>G | p.Asn558Ser | missense_variant | 15/21 | NM_000441.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250834Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135558
GnomAD4 exome AF: 0.0000104 AC: 15AN: 1439224Hom.: 0 Cov.: 26 AF XY: 0.00000975 AC XY: 7AN XY: 717600
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 558 of the SLC26A4 protein (p.Asn558Ser). This variant is present in population databases (rs766206507, gnomAD 0.03%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 28964290; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 597784). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn558 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 29501320), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34652575, 28964290) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 12, 2018 | - - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pendred syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at