12-51916113-A-G

Position:

• chr12-51916113-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1126A>G​(p.Met376Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M376R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51916114-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8244.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.993
• PP5: Variant 12-51916113-A-G is Pathogenic according to our data. Variant chr12-51916113-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51916113-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.1126A>G	p.Met376Val	missense_variant	8/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1126A>G	p.Met376Val	missense_variant	8/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 29, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 376 of the ACVRL1 protein (p.Met376Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15024723, 16123970, 16690726, 17384219, 17786384). ClinVar contains an entry for this variant (Variation ID: 464754). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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: 15024723, 17384219, 17786384, 16690726, 15266205, 32300199, 16123970) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2023

The p.M376V pathogenic mutation (also known as c.1126A>G), located in coding exon 7 of the ACVRL1 gene, results from an A to G substitution at nucleotide position 1126. The methionine at codon 376 is replaced by valine, an amino acid with highly similar properties. This mutation has been reported in a patient with epistaxis, telangiectasias, gastrointestinal bleeding, liver arteriovenous malformations, and family history (Argyriou L et al., Liver Transpl. 2005; 11(9):1132-5). This variant has also been detected in hereditary hemorrhagic telangiectasia (HHT) cohorts (Prigoda NL et al. J Med Genet. 2006 Sep;43(9):722-8; McDonald J et al. Genet Med. 2020 07;22(7):1201-1205). Other alterations at the same amino acid position, p.M376K (Olivieri C et al, Genet. Med. 2006 Mar; 8(3):183-90), p.M376T (Fernandez-L A et al, Hum. Mutat. 2006 Mar; 27(3):295), and p.M376R (Johnson DW et al, Nat. Genet. 1996 Jun; 13(2):189-95) have also been reported in association with HHT. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.98		Loss of sheet (P = 0.1158);.;.;
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1555153277; hg19: chr12-52309897;