rs706815

Positions:

• chr12-51919160-T-C

Variant summary

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

The ENST00000388922.9(ACVRL1):​c.1377+45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,612,628 control chromosomes in the GnomAD database, including 56,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8354 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48471 hom.)
• Consequence: ACVRL1 ENST00000388922.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.824

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=-0.85).
• BP6: Variant 12-51919160-T-C is Benign according to our data. Variant chr12-51919160-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 254709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51919160-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1377+45T>C		intron_variant		ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1377+45T>C		intron_variant		1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47310 AN: 151594 Hom.: 8333 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.264 AC: 65716 AN: 248984 Hom.: 9332 AF XY: 0.258 AC XY: 34723 AN XY: 134746

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.423

Gnomad SAS exome AF: 0.232

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.252 AC: 367933 AN: 1460916 Hom.: 48471 Cov.: 35 AF XY: 0.251 AC XY: 182227 AN XY: 726724

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.436

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.312 AC: 47370 AN: 151712 Hom.: 8354 Cov.: 32 AF XY: 0.309 AC XY: 22872 AN XY: 74122

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.299

Alfa AF: 0.263 Hom.: 1462

Bravo AF: 0.322

Asia WGS AF: 0.346 AC: 1200 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.39

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

Other links and lift over

dbSNP: rs706815; hg19: chr12-52312944;