12-51920817-G-A

Position:

chr12-51920817-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000020.3(ACVRL1):c.1436G>A(p.Arg479Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R479P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.99

Variant links:

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]

ACVRL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chr12-51920817-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 426036.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 12-51920817-G-A is Pathogenic according to our data. Variant chr12-51920817-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3 linkuse as main transcript	c.1436G>A	p.Arg479Gln	missense_variant	10/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9 linkuse as main transcript	c.1436G>A	p.Arg479Gln	missense_variant	10/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2018	The ACVRL1 c.1436G>A;p.Arg479Gln variant has been described in families and individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) and has been described as segregating with disease (Bayrak-Toydemir 2006, Bayrak-Toydemir 2008, Fujiwara 2008, Gedge 2007, Lesca 2006, McDonald 2011). It is reported as pathogenic in ClinVar (Variation ID: 426035) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 479 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. Additionally, this variant has been shown to have reduced function (Ricard 2010). Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006 Mar 1;140(5):463-70. Bayrak-Toydemir P et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008 Aug;85(1):45-9.. Fujiwara M et al. Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J. 2008 Jan;72(1):127-33. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 09, 2023	The ACVRL1 c.1436G>A variant is classified as Likely Pathogenic (PS4_Moderate, PM2_supporting, PS3_supporting, PM1_supporting, PP3). The ACVRL1 c.1436G>A variant is a single nucleotide change in exon 10/10 of the ACVRL1 gene, which is predicted to change the amino acid arginine at position 479 in the protein to glutamine. The variant has been reported in multiple individuals with a clinical presentation of HHT (PMID:34872578, PMID:32300199, PMID:16705692) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 151854 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2_supporting). Functional studies show a deleterious effect of this variant (PMID:20501893) (PS3_supporting). This variant is located in the conserved serine/threonine kinase domain (PMID:34872578) (PM1_supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs1085307426) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 426035). It has not been reported in HGMD. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 479 of the ACVRL1 protein (p.Arg479Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 16470787, 16705692, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426035). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 21, 2022

PP1_strong, PP3, PP4, PM2_supporting, PS3_supporting, PS4_moderate -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The p.R479Q pathogenic mutation (also known as c.1436G>A), located in coding exon 9 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1436. The arginine at codon 479 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals meeting clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (Bayrak-Toydemir P et al. Am. J. Med. Genet. A, 2006 Mar;140:463-70; Lesca G et al. Hum. Mutat., 2006 Jun;27:598; Giordano P et al. J. Pediatr., 2013 Jul;163:179-86.e1-3) and it has been shown to co-segregate with disease (Bayrak-Toydemir P et al. Exp. Mol. Pathol., 2008 Aug;85:45-9). In addition, an in vitro functional study demonstrated that although this mutation does not disrupt ligand binding, it does interfere with ligand signaling (Ricard N et al. Blood, 2010 Sep;116:1604-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Pulmonary hypertension, primary, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.8

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.96

MutPred

0.98

Loss of MoRF binding (P = 0.0311);.;.;

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

4.4

Varity_R

0.96

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over