rs1085307415

Variant names:

• chr12-51916042-C-A
• rs1085307415
• NM_000020.3:c.1055C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51916042-C-A
• chr12-51916042-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1055C>A​(p.Ala352Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. A352V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.90
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• hereditary hemorrhagic telangiectasia

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr12-51916042-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2750999.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-51916042-C-A is Pathogenic according to our data. Variant chr12-51916042-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1055C>A	p.Ala352Asp	missense_variant	Exon 8 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1055C>A	p.Ala352Asp	missense_variant	Exon 8 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726062

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110908

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Jan 04, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 426023). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 16690726, 19357124; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 352 of the ACVRL1 protein (p.Ala352Asp). -

Cardiovascular phenotype Pathogenic:1

Nov 15, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A352D variant (also known as c.1055C>A), located in coding exon 7 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 1055. This variant was identified in two unrelated individuals with epistaxis, telangiectasias, pulmonary arterial hypertension, and arteriovenous malformations (Smoot LB et al. Arch. Dis. Child., 2009 Jul;94:506-11). This variant was also reported in individuals with epistaxis and positive family history of hereditary hemorrhagic telangiectasia (Prigoda NL et al. J. Med. Genet., 2006 Sep;43:722-8; Song J et al. Clin. Sci., 2016 Nov;130:2043-2052). The alanine at codon 352 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, 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	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.3	H;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.91	P;.;D
Vest4		1.0
MutPred		0.98		Gain of disorder (P = 0.0898);.;.;
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1085307415; hg19: chr12-52309826;