Variant rs758683062 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000020.3(ACVRL1):c.430C>T(p.Arg144Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,930 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACVRL1
NM_000020.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.959

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-51913675-C-T is Pathogenic according to our data. Variant chr12-51913675-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 212804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51913675-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3 linkuse as main transcript	c.430C>T	p.Arg144Ter	stop_gained	4/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9 linkuse as main transcript	c.430C>T	p.Arg144Ter	stop_gained	4/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725480

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2021	The ACVRL1 c.430C>T; p.Arg144Ter variant (rs758683062) is reported in the literature in multiple individuals diagnosed with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension (Abdalla 2003, Abdalla 2005, Brusgaard 2004, Canzonieri 2014, Giordano 2006, Kjeldsen 2005, Komiyama 2014, Lesca 2004, Machado 2009, Olivieri 2007, Schulte 2005). This variant is reported in ClinVar as pathogenic by multiple laboratories (Variation ID: 212804), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003; 11(4):279-87. PMID: 12700602. Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005; 25(3):320-1. PMID: 15712271. Brusgaard K et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004; 66(6):556-61. PMID: 15521985. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014; 16(1):3-10. PMID: 23722869. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006; 4(6):1237-45. PMID: 16706966. Kjeldsen AD et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med. 2005; 258(4):349-55. PMID: 16164574. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014; 59(1):37-41. PMID: 24196379. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004; 23(4):289-99. PMID: 15024723. Machado RD et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S32-42. PMID: 19555857. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007; 52(10):820-9. PMID: 17786384. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005; 25(6):595. PMID: 15880681. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change creates a premature translational stop signal (p.Arg144*) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension (PMID: 12700602, 15024723, 15879500, 15880681, 16429404, 16540754, 19555857, 23722869). ClinVar contains an entry for this variant (Variation ID: 212804). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change creates a premature termination codon at position 144 in exon 4 (of 10) of ACVRL1 (p.(Arg144*)). It is expected to result in nonsense mediated decay, and loss of function is well-established mechanism of disease for this gene (ClinVar). The variant is present in a single individual in a large population cohort (1/246,414 alleles in gnomAD v2.1 and absent in gnomAD v3.1), which is consistent with dominant condition. The variant is a recurrent mutation that has been identified in multiple cases with a clinical diagnosis of hereditary haemorrhagic telangiectasia and segregates with disease in at least one four-generation family (PMID: 12700602, 15024723, 15880681, 16429404, 23722869). It has also been identified in at least one individual with idiopathic pulmonary arterial hypertension (PMID: 19555857). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PP1_Strong, PM2_Supporting. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 11, 2022	PM2_supporting, PS4_moderate, PVS1 -

Pulmonary hypertension, primary, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The p.R144* pathogenic mutation (also known as c.430C>T), located in coding exon 3 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 430. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was first described in an individual with epistaxis, telangiectasias, and a family history of hereditary hemorrhagic telangiectasia (HHT) (Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87). This mutation has also been described in several French HHT families (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99). Other studies identified this mutation in two individuals with multiple telangiectasias in the gastrointestinal tract, epistaxis, and pulmonary arteriovenous malformations (Canzonieri C et al. Genet Med. 2014;16(1):3-10; Verhelst X et al. Case Rep Gastroenterol Jan;12:13-18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Benign

0.60

MutationTaster

Benign

1.0

A;A;D

Vest4

0.91

GERP RS

4.7

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

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