rs2071219

chr12-51913524-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000020.3(ACVRL1):c.314-35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,579,214 control chromosomes in the GnomAD database, including 158,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16787 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141297 hom.)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.227

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-51913524-A-G is Benign according to our data. Variant chr12-51913524-A-G is described in ClinVar as [Benign]. Clinvar id is 254710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51913524-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.314-35A>G		intron_variant		ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.314-35A>G		intron_variant		1	NM_000020.3	P1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70261 AN: 151906 Hom.: 16775 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.440

GnomAD3 exomes AF: 0.404 AC: 82874 AN: 204938 Hom.: 17797 AF XY: 0.415 AC XY: 46722 AN XY: 112590

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.467

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.441 AC: 629800 AN: 1427190 Hom.: 141297 Cov.: 39 AF XY: 0.443 AC XY: 314268 AN XY: 708856

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.449

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.463 AC: 70314 AN: 152024 Hom.: 16787 Cov.: 32 AF XY: 0.460 AC XY: 34146 AN XY: 74300

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.439

Alfa AF: 0.458 Hom.: 3005

Bravo AF: 0.451

Asia WGS AF: 0.392 AC: 1365 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

This variant is associated with the following publications: (PMID: 16179574, 16776339, 25847705) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	7.5
Dann	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2071219; hg19: chr12-52307308; COSMIC: COSV66360449; COSMIC: COSV66360449;