rs863223408
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_000020.3(ACVRL1):c.1451G>A(p.Arg484Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
ACVRL1
NM_000020.3 missense
NM_000020.3 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 9.99
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 15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACVRL1. . Gene score misZ 2.4458 (greater than the threshold 3.09). Trascript score misZ 3.182 (greater than threshold 3.09). GenCC has associacion of gene with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 12-51920832-G-A is Pathogenic according to our data. Variant chr12-51920832-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 212796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51920832-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACVRL1 | NM_000020.3 | c.1451G>A | p.Arg484Gln | missense_variant | 10/10 | ENST00000388922.9 | NP_000011.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACVRL1 | ENST00000388922.9 | c.1451G>A | p.Arg484Gln | missense_variant | 10/10 | 1 | NM_000020.3 | ENSP00000373574 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 04, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 484 of the ACVRL1 protein (p.Arg484Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary haemorrhagic telangiectasia or pulmonary arterial hypertension (PMID: 15687131, 17786384, 18159113, 21378382, 22632830, 23298310, 23919827). ClinVar contains an entry for this variant (Variation ID: 212796). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). This variant disrupts the p.Arg484 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11484689, 16540754, 18498373, 20056902, 20501893, 23124896, 27316748). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Sep 26, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
Pulmonary arterial hypertension Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 04, 2016 | - - |
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 | - | - - |
Epistaxis;C2973725:Pulmonary arterial hypertension Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 24, 2015 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that variants in residue 484, which is located in the highly conserved NANDOR box region, cause defective signaling with the BMP9 ligand (Ricard et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21378382, 17786384, 23919827, 22632830, 18159113, 23298310, 29631995, 26387786, 20501893, 27587546, 31630786, 30578397, 30578106, 31511490, 32170914, 32581362, 34966542, 15687131) - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2022 | The p.R484Q pathogenic mutation (also known as c.1451G>A), located in coding exon 9 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1451. The arginine at codon 484 is replaced by glutamine, an amino acid with highly similar properties. In one study of 18 children with pulmonary arterial hypertension (PAH), this mutation was detected in an individual with idiopathic PAH, but with no manifestations of hereditary hemorrhagic telangiectasia (HHT) at 5 years old (Harrison RE et al. Circulation, 2005 Feb;111:435-41). This mutation was also reported in a family in which two mutation carriers showed symptoms of PAH and one of HHT; there was also one unaffected mutation carrier in the family (Pfarr N et al. Respir. Res., 2013;14:3). Furthermore, this mutation was described in an individual with PAH and HHT (Chen YJ et al. Eur. J. Clin. Invest., 2013 Oct;43:1016-24). The p.R484Q mutation is located in the intracellular kinase domain in the NANDOR box of the ALK1 protein, and functional studies showed this mutation had no functional activity in response to BMP9, a ligand for ALK1 (Ricard N et al. Blood, 2010 Sep;116:1604-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;T
Polyphen
D;.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0549);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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