rs2227861

chr2-157780398-G-Achr2-157780398-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001111067.4(ACVR1):c.270C>T(p.Ala90=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,613,950 control chromosomes in the GnomAD database, including 465,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (34999 hom., cov: 31)
  • Exomes 𝑓: 0.76 (430081 hom.)
• Consequence: ACVR1 NM_001111067.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.73

Genes affected

ACVR1 (HGNC:171): (activin A receptor type 1) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-157780398-G-A is Benign according to our data. Variant chr2-157780398-G-A is described in ClinVar as [Benign]. Clinvar id is 257464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-157780398-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR1	NM_001111067.4	c.270C>T	p.Ala90=	synonymous_variant	4/11	ENST00000434821.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1	ENST00000434821.7	c.270C>T	p.Ala90=	synonymous_variant	4/11	1	NM_001111067.4	P4

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96988 AN: 151972 Hom.: 34987 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.664

GnomAD3 exomes AF: 0.762 AC: 191486 AN: 251244 Hom.: 75599 AF XY: 0.772 AC XY: 104825 AN XY: 135774

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.927

Gnomad SAS exome AF: 0.827

Gnomad FIN exome AF: 0.781

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.762 AC: 1113826 AN: 1461860 Hom.: 430081 Cov.: 73 AF XY: 0.765 AC XY: 556230 AN XY: 727232

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.818

Gnomad4 ASJ exome AF: 0.805

Gnomad4 EAS exome AF: 0.918

Gnomad4 SAS exome AF: 0.827

Gnomad4 FIN exome AF: 0.783

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.752

GnomAD4 genome AF: 0.638 AC: 97018 AN: 152090 Hom.: 34999 Cov.: 31 AF XY: 0.645 AC XY: 47978 AN XY: 74330

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.758

Gnomad4 ASJ AF: 0.802

Gnomad4 EAS AF: 0.923

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.666

Alfa AF: 0.711 Hom.: 20568

Bravo AF: 0.614

Asia WGS AF: 0.836 AC: 2907 AN: 3478

EpiCase AF: 0.765

EpiControl AF: 0.764

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myositis ossificans Benign:2

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-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.1
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2227861; hg19: chr2-158636910; COSMIC: COSV99717425; COSMIC: COSV99717425;