12-51916183-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000020.3(ACVRL1):​c.1196G>T​(p.Trp399Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

ACVRL1
NM_000020.3 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.99
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a helix (size 20) in uniprot entity ACVL1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000020.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 12-51916183-G-T is Pathogenic according to our data. Variant chr12-51916183-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 426027.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACVRL1NM_000020.3 linkc.1196G>T p.Trp399Leu missense_variant Exon 8 of 10 ENST00000388922.9 NP_000011.2 P37023A0A0S2Z310

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACVRL1ENST00000388922.9 linkc.1196G>T p.Trp399Leu missense_variant Exon 8 of 10 1 NM_000020.3 ENSP00000373574.4 P37023

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1
-
Rare Disease Genomics Group, St George's University of London
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;.;D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-7.5
D;D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;.;P
Vest4
0.96
MutPred
0.85
Loss of methylation at K394 (P = 0.0803);.;.;
MVP
0.98
MPC
2.1
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.96
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121909289; hg19: chr12-52309967; API