rs1058563

Positions:

• chr12-51914560-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000020.3(ACVRL1):​c.747G>A​(p.Val249=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,613,684 control chromosomes in the GnomAD database, including 702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (369 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (333 hom.)
• Consequence: ACVRL1 NM_000020.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.271

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 12-51914560-G-A is Benign according to our data. Variant chr12-51914560-G-A is described in ClinVar as [Benign]. Clinvar id is 212793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51914560-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.747G>A	p.Val249=	synonymous_variant	6/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.747G>A	p.Val249=	synonymous_variant	6/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5869 AN: 152022 Hom.: 365 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0110 AC: 2755 AN: 250532 Hom.: 138 AF XY: 0.00811 AC XY: 1098 AN XY: 135450

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00503 AC: 7346 AN: 1461542 Hom.: 333 Cov.: 32 AF XY: 0.00452 AC XY: 3289 AN XY: 727050

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.00991

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0387 AC: 5885 AN: 152142 Hom.: 369 Cov.: 33 AF XY: 0.0384 AC XY: 2854 AN XY: 74378

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0209 Hom.: 112

Bravo AF: 0.0436

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val249Val in exon 6 of ACVRL1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 13.1% (576/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1058563). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2015

This alteration is classified as 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1058563; hg19: chr12-52308344;