12-51920826-C-T

Variant names:

• chr12-51920826-C-T
• rs139142865
• NM_000020.3:c.1445C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. BP5 BS1 PP3 PM5 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000020.3: c.1445C>T variant in ACVRL1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 482 (p.Ala482Val). Another missense variant, c.1445C>A, Ala482Glu (PMID:17786384, 21158752), in the same codon has been classified as likely pathogenic for autosomal dominant Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). However, the filtering allele frequency (the lower threshold of the 95% CI of 395/129122) of the c.1445C>T variant in ACVRL1 is 0.002819 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has also been observed in 3 patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ENG variant) (BP5; PMID:15517393, Internal lab contributors). The computational predictor REVEL gives a score of 0.839, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). However, functional assays (BRE assay, Western blot analysis of Smad1/5 phosphorylation) in NIH-3T3 cells showed that the variant protein responded to BMP9 stimulation either measured in the BRE assay or by Smad1/5 phosphorylation, indicating that this variant does not impact protein function (BS3_Supporting; PMID:20501893). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting, PP3, PM5 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211324/MONDO:0010880/135

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:16
• Conservation: PhyloP100: 6.07
• Publications: 16 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: Likely_benign. The variant received -3 ACMG points.

• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000020.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.1445C>T	p.Ala482Val	missense	Exon 10 of 10	NP_000011.2
	ACVRL1	NM_001077401.2		c.1445C>T	p.Ala482Val	missense	Exon 9 of 9	NP_001070869.1
	ACVRL1	NM_001406487.1		c.1445C>T	p.Ala482Val	missense	Exon 11 of 11	NP_001393416.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1445C>T	p.Ala482Val	missense	Exon 10 of 10	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.1487C>T	p.Ala496Val	missense	Exon 9 of 9	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.1445C>T	p.Ala482Val	missense	Exon 11 of 11	ENSP00000455848.2

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 151918 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00155 AC: 390 AN: 251426 AF XY: 0.00160

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00327 AC: 4784 AN: 1461500 Hom.: 16 Cov.: 35 AF XY: 0.00316 AC XY: 2296 AN XY: 727054

African (AFR) AF: 0.000478 AC: 16 AN: 33468

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00412 AC: 4581 AN: 1111784

Other (OTH) AF: 0.00202 AC: 122 AN: 60360

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152032 Hom.: 0 Cov.: 31 AF XY: 0.00198 AC XY: 147 AN XY: 74324

African (AFR) AF: 0.000506 AC: 21 AN: 41512

American (AMR) AF: 0.00170 AC: 26 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00359 AC: 244 AN: 67952

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00263 Hom.: 0

Bravo AF: 0.00193

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00273

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:7

Aug 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 09, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Mar 15, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000020.3: c.1445C>T variant in ACVRL1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 482 (p.Ala482Val). Another missense variant, c.1445C>A, Ala482Glu (PMID: 17786384, 21158752), in the same codon has been classified as likely pathogenic for autosomal dominant Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). However, the filtering allele frequency (the lower threshold of the 95% CI of 395/129122) of the c.1445C>T variant in ACVRL1 is 0.002819 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has also been observed in 3 patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ENG variant) (BP5; PMID: 15517393, Internal lab contributors). The computational predictor REVEL gives a score of 0.839, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). However, functional assays (BRE assay, Western blot analysis of Smad1/5 phosphorylation) in NIH-3T3 cells showed that the variant protein responded to BMP9 stimulation either measured in the BRE assay or by Smad1/5 phosphorylation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting, PP3, PM5 (specification version 1.0.0; 1/4/2024).

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:5

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACVRL1: BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10323406, 15024723, 18285823, 24055113, 20501893, 25637381, 24082139, 15880681, 19767588, 15517393, 16690726, 15879500, 27316748)

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Pulmonary arterial hypertension Uncertain:1

Sep 26, 2022

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

not specified Benign:1

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in multiple control cohorts; ExAC: 0.3% (190/66476) European chromosomes

Haemorrhagic telangiectasia 2 Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

ACVRL1-related disorder Benign:1

Feb 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Cardiovascular phenotype Benign:1

Jun 22, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.97
MPC		1.5
ClinPred		0.039	T
GERP RS		3.5
Varity_R		0.59
gMVP		0.94
Mutation Taster		=68/32	polymorphism

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: rs139142865; hg19: chr12-52314610;