rs1085307416
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000020.3(ACVRL1):c.1124A>G(p.Tyr375Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 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. Y375F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000020.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.1124A>G | p.Tyr375Cys | missense_variant | 8/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.1124A>G | p.Tyr375Cys | missense_variant | 8/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the ACVRL1 protein (p.Tyr375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) and/or pulmonary arterial hypertension (PMID: 23919827; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426024). 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 ACVRL1 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr375 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12843319). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at