chr6-135447094-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001134831.2(AHI1):c.1693C>T(p.Arg565Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R565H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001134831.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AHI1 | NM_001134831.2 | c.1693C>T | p.Arg565Cys | missense_variant | 13/29 | ENST00000265602.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AHI1 | ENST00000265602.11 | c.1693C>T | p.Arg565Cys | missense_variant | 13/29 | 1 | NM_001134831.2 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248706Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134932
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460498Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 726536
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74430
ClinVar
Submissions by phenotype
Joubert syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 19, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 565 of the AHI1 protein (p.Arg565Cys). This variant is present in population databases (rs763970632, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AHI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 241183). 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 not expected to disrupt AHI1 protein function. 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