rs199717203
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001127198.5(TMC6):c.890C>T(p.Ala297Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 1,610,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A297T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001127198.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC6 | NM_001127198.5 | c.890C>T | p.Ala297Val | missense_variant, splice_region_variant | 8/20 | ENST00000590602.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC6 | ENST00000590602.6 | c.890C>T | p.Ala297Val | missense_variant, splice_region_variant | 8/20 | 2 | NM_001127198.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000532 AC: 81AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000442 AC: 105AN: 237474Hom.: 0 AF XY: 0.000466 AC XY: 61AN XY: 131002
GnomAD4 exome AF: 0.000622 AC: 906AN: 1457730Hom.: 0 Cov.: 33 AF XY: 0.000647 AC XY: 469AN XY: 725242
GnomAD4 genome ? AF: 0.000532 AC: 81AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40AN XY: 74472
ClinVar
Submissions by phenotype
Epidermodysplasia verruciformis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 297 of the TMC6 protein (p.Ala297Val). This variant is present in population databases (rs199717203, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 456019). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at