rs1301762186

Positions:

• chr12-51920794-C-A
• chr12-51920794-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1413C>A​(p.Cys471Ter) 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.76

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 14 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. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51920794-C-A is Pathogenic according to our data. Variant chr12-51920794-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 464759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1413C>A	p.Cys471Ter	stop_gained	10/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1413C>A	p.Cys471Ter	stop_gained	10/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ACVRL1 protein. Other variant(s) that disrupt this region (p.Arg479*) have been determined to be pathogenic (PMID: 15024723, 16540754, 23722869). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 16752392, 22991266, 26401274). ClinVar contains an entry for this variant (Variation ID: 464759). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ACVRL1 gene (p.Cys471*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acids of the ACVRL1 protein. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2017

The p.C471* pathogenic mutation (also known as c.1413C>A), located in coding exon 9 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 1413. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This mutation was detected in multiple individual with clinical features of hereditary hemorrhagic telangiectasia (HHT), including one individual with epistaxis, telangiectasias, arteriovenous malformations, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34; Kuchtey RW et al. Clin Case Rep, 2015 Sep;3:725-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.88
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1301762186; hg19: chr12-52314578;