rs1085307429
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000020.3(ACVRL1):c.1468C>T(p.Gln490Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q490Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
ACVRL1
NM_000020.3 stop_gained
NM_000020.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 0.328
Genes affected
ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0291 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-51920849-C-T is Pathogenic according to our data. Variant chr12-51920849-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 426040.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.1468C>T | p.Gln490Ter | stop_gained | 10/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.1468C>T | p.Gln490Ter | stop_gained | 10/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2018 | PVS1+PM2+PP4 - |
Pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen | Mar 15, 2024 | The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 15879500, 16829353, 20301525). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 16829353, 16540754, 32573726, 11484689, Internal lab contributors). The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID: 16829353, 11484689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PS4, PP1_Strong (specification version 1.0.0; 1/4/2024). - |
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 | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 28, 2023 | PP1_strong, PM2_supporting, PS4, PVS1_moderate - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2021 | The p.Q490* pathogenic mutation (also known as c.1468C>T), located in coding exon 9 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1468. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theACVRL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 2.8% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT), as well as in individuals with concerns for HHT (El-Harith et al. Eur J Med Genet 2006 Oct;49:323-30; Lenato GM et al. Hum Mutat, 2006 Feb;27:213-4; Olivieri C et al. Genet Med, 2006 Mar;8:183-90; Tørring PM et al. Clin Genet, 2014 Aug;86:123-33). Additionally, this alteration segregated with disease in one family (Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at