rs77341011

chr12-51913575-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000020.3(ACVRL1):c.330G>A(p.Ser110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,598,474 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (53 hom.)
• Consequence: ACVRL1 NM_000020.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.297

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 12-51913575-G-A is Benign according to our data. Variant chr12-51913575-G-A is described in ClinVar as [Benign]. Clinvar id is 212791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51913575-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2069/152342) while in subpopulation AFR AF= 0.0407 (1692/41580). AF 95% confidence interval is 0.0391. There are 39 homozygotes in gnomad4. There are 970 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2064 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.330G>A	p.Ser110=	synonymous_variant	4/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.330G>A	p.Ser110=	synonymous_variant	4/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2064 AN: 152224 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0407

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00468 AC: 1099 AN: 234742 Hom.: 17 AF XY: 0.00383 AC XY: 493 AN XY: 128666

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00419

GnomAD4 exome AF: 0.00354 AC: 5113 AN: 1446132 Hom.: 53 Cov.: 34 AF XY: 0.00325 AC XY: 2336 AN XY: 719834

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.00383

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000442

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.0136 AC: 2069 AN: 152342 Hom.: 39 Cov.: 33 AF XY: 0.0130 AC XY: 970 AN XY: 74484

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00828 Hom.: 1

Bravo AF: 0.0152

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00232

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2016

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	-0.81
Cadd	Benign	18
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77341011; hg19: chr12-52307359;