12-51913330-A-G

Position:

• chr12-51913330-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000020.3(ACVRL1):​c.293A>G​(p.Asn98Ser) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.15

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. GenCC has associacion of the gene with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 12-51913330-A-G is Pathogenic according to our data. Variant chr12-51913330-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426011.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.293A>G	p.Asn98Ser	missense_variant	3/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.293A>G	p.Asn98Ser	missense_variant	3/10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 98 of the ACVRL1 protein (p.Asn98Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (HHT) (PMID: 16690726, 18498373, 32503579; Invitae). ClinVar contains an entry for this variant (Variation ID: 426011). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2015

The p.N98S variant (also known as c.293A>G), located in coding exon 2 of the ACVRL1 gene, results from an A to G substitution at nucleotide position 293. The asparagine at codon 98 is replaced by serine, an amino acid with highly similar properties. There have been two independent reports of individuals heterozygous for this alteration: one presented with telangiectases and severe hepatic arteriovenous malformations (HAVMs) (Prigoda NL et al, J. Med. Genet. 2006 Sep; 43(9):722-8) and the other with focal nodular hyperplasia and typical HAVMs (Brakensiek K et al, Clin. Genet. 2008 Aug; 74(2):171-7). Although both were reported to have hereditary hemorrhagic telangiectasia (HHT), insufficient information was provided in the primary reports to confirm a definite diagnosis based on Curacoa’s diagnostic criteria. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D;T;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.064	T;D;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.91	P;.;.
Vest4		0.52
MutPred		0.86		Gain of disorder (P = 0.0906);.;.;
MVP		0.94
MPC		0.99
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.34
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307406; hg19: chr12-52307114;