12-51916108-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000020.3(ACVRL1):c.1121G>C(p.Arg374Pro) 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. R374Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr12-51916108-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 411314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ACVRL1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 12-51916108-G-C is Pathogenic according to our data. Variant chr12-51916108-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 533351.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.1121G>C	p.Arg374Pro	missense_variant	8/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1121G>C	p.Arg374Pro	missense_variant	8/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 374 of the ACVRL1 protein (p.Arg374Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 533351). 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. This variant disrupts the p.Arg374 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9245985, 12700602, 18285823, 20501893, 21158752, 22991266, 23722869, 25970827). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MutPred		0.88		Loss of methylation at R374 (P = 0.0273);.;.;
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.98

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

Other links and lift over

dbSNP: rs1060503248; hg19: chr12-52309892;