rs4294956

Variant names:

• chr2-157811942-T-C
• rs4294956
• NM_001111067.4:c.-8+6443A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001111067.4(ACVR1):​c.-8+6443A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,186 control chromosomes in the GnomAD database, including 4,637 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (4637 hom., cov: 33)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.-8+6443A>G		intron_variant	Intron 2 of 10	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.-8+6443A>G		intron_variant	Intron 2 of 10	1	NM_001111067.4	ENSP00000405004.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20448 AN: 152068 Hom.: 4622 Cov.: 33

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.00982

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.103

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.135 AC: 20506 AN: 152186 Hom.: 4637 Cov.: 33 AF XY: 0.130 AC XY: 9692 AN XY: 74432

African (AFR) AF: 0.466 AC: 19329 AN: 41452

American (AMR) AF: 0.0525 AC: 803 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00982 AC: 34 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68026

Other (OTH) AF: 0.102 AC: 216 AN: 2108

Alfa AF: 0.0831 Hom.: 354

Bravo AF: 0.154

Asia WGS AF: 0.0320 AC: 113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0070
DANN	Benign	0.36
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4294956; hg19: chr2-158668454;