rs2227861

Variant names:

• chr2-157780398-G-A
• rs2227861
• NM_001111067.4:c.270C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-157780398-G-A
• chr2-157780398-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001111067.4(ACVR1):​c.270C>T​(p.Ala90Ala) 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:6
• Conservation: PhyloP100: -1.73
• Publications: 29 publications found

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]

ACVR1 Gene-Disease associations (from GenCC):

• fibrodysplasia ossificans progressiva

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	NM_001111067.4	MANE Select	c.270C>T	p.Ala90Ala	synonymous	Exon 4 of 11	NP_001104537.1	D3DPA4
	ACVR1	NM_001105.5		c.270C>T	p.Ala90Ala	synonymous	Exon 4 of 11	NP_001096.1	D3DPA4
	ACVR1	NM_001347663.1		c.270C>T	p.Ala90Ala	synonymous	Exon 4 of 11	NP_001334592.1	Q04771

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.270C>T	p.Ala90Ala	synonymous	Exon 4 of 11	ENSP00000405004.1	Q04771
	ACVR1	ENST00000263640.7	TSL:1	c.270C>T	p.Ala90Ala	synonymous	Exon 4 of 11	ENSP00000263640.3	Q04771
	ACVR1	ENST00000410057.6	TSL:1	c.270C>T	p.Ala90Ala	synonymous	Exon 5 of 12	ENSP00000387127.2	Q04771

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

GnomAD2 exomes AF: 0.762 AC: 191486 AN: 251244 AF XY: 0.772

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 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

African (AFR) AF: 0.242 AC: 8101 AN: 33480

American (AMR) AF: 0.818 AC: 36594 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 21041 AN: 26136

East Asian (EAS) AF: 0.918 AC: 36429 AN: 39700

South Asian (SAS) AF: 0.827 AC: 71298 AN: 86256

European-Finnish (FIN) AF: 0.783 AC: 41821 AN: 53420

Middle Eastern (MID) AF: 0.757 AC: 4364 AN: 5768

European-Non Finnish (NFE) AF: 0.763 AC: 848748 AN: 1111980

Other (OTH) AF: 0.752 AC: 45430 AN: 60396

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

African (AFR) AF: 0.271 AC: 11228 AN: 41426

American (AMR) AF: 0.758 AC: 11583 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2782 AN: 3470

East Asian (EAS) AF: 0.923 AC: 4777 AN: 5176

South Asian (SAS) AF: 0.827 AC: 3988 AN: 4822

European-Finnish (FIN) AF: 0.779 AC: 8250 AN: 10592

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52163 AN: 68004

Other (OTH) AF: 0.666 AC: 1404 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Progressive myositis ossificans (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.71
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227861; hg19: chr2-158636910; COSMIC: COSV99717425; COSMIC: COSV99717425;