rs80356459
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_005982.4(SIX1):c.328C>T(p.Arg110Trp) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110Q) has been classified as Pathogenic.
Frequency
Consequence
NM_005982.4 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIX1 | NM_005982.4 | c.328C>T | p.Arg110Trp | missense_variant | Exon 1 of 2 | ENST00000645694.3 | NP_005973.1 | |
SIX1 | NM_001425142.1 | c.328C>T | p.Arg110Trp | missense_variant | Exon 1 of 2 | NP_001412071.1 | ||
MIR9718 | NR_162089.1 | n.*151G>A | downstream_gene_variant | |||||
MIR9718 | unassigned_transcript_2330 | n.*162G>A | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIX1 | ENST00000645694.3 | c.328C>T | p.Arg110Trp | missense_variant | Exon 1 of 2 | NM_005982.4 | ENSP00000494686.1 | |||
SIX1 | ENST00000554986.2 | c.42-2285C>T | intron_variant | Intron 1 of 1 | 3 | ENSP00000452700.2 | ||||
SIX1 | ENST00000553535.2 | n.249-2285C>T | intron_variant | Intron 2 of 2 | 3 | |||||
SIX1 | ENST00000555955.3 | n.1198-2285C>T | intron_variant | Intron 1 of 1 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Branchiootic syndrome 3 Pathogenic:1Other:1
- -
- -
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 110 of the SIX1 protein (p.Arg110Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SIX1-related conditions (PMID: 15141091, 24164807; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8309). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SIX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SIX1 function (PMID: 15141091, 19497856, 31980437). This variant disrupts the p.Arg110 amino acid residue in SIX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
SIX1: PS1, PM2, PS3:Moderate, PP3, PS4:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at