rs1555152966

Positions:

• chr12-51914585-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000388922.9(ACVRL1):​c.772G>A​(p.Gly258Ser) variant causes a missense, splice region 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 ENST00000388922.9 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.73

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 15 ACMG points.

• PM1: In a domain Protein kinase (size 290) in uniprot entity ACVL1_HUMAN there are 240 pathogenic changes around while only 13 benign (95%) in ENST00000388922.9
• 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, 0.903
• PP5: Variant 12-51914585-G-A is Pathogenic according to our data. Variant chr12-51914585-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 444101.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.772G>A	p.Gly258Ser	missense_variant, splice_region_variant	6/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.772G>A	p.Gly258Ser	missense_variant, splice_region_variant	6/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2022

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 444101). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677, 31220907; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 258 of the ACVRL1 protein (p.Gly258Ser). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetics, Medical University of Vienna

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- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2024

The c.772G>A variant (also known as p.G258S), located in coding exon 5 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 772. The glycine at codon 258 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in individuals reported to have hereditary hemorrhagic telangiectasia (Koenighofer M et al. Clin Exp Otorhinolaryngol, 2019 Nov;12:405-411; Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.032	D;D;T
Polyphen		1.0	D;.;D
Vest4		0.89
MutPred		0.47		Gain of disorder (P = 0.0933);.;.;
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.83
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555152966; hg19: chr12-52308369;