rs1220134

Variant names:

• chr2-157747044-T-A
• rs1220134
• NM_001111067.4:c.1265-8474A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001111067.4(ACVR1):​c.1265-8474A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,058 control chromosomes in the GnomAD database, including 13,643 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 0.38 (13643 hom., cov: 32)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	NM_001111067.4	MANE Select	c.1265-8474A>T		intron	N/A	NP_001104537.1
	ACVR1	NM_001105.5		c.1265-8474A>T		intron	N/A	NP_001096.1
	ACVR1	NM_001347663.1		c.1265-8474A>T		intron	N/A	NP_001334592.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.1265-8474A>T		intron	N/A	ENSP00000405004.1
	ACVR1	ENST00000263640.7	TSL:1	c.1265-8474A>T		intron	N/A	ENSP00000263640.3
	ACVR1	ENST00000410057.6	TSL:1	c.1265-8474A>T		intron	N/A	ENSP00000387127.2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57244 AN: 151940 Hom.: 13602 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.377 AC: 57341 AN: 152058 Hom.: 13643 Cov.: 32 AF XY: 0.369 AC XY: 27436 AN XY: 74334

African (AFR) AF: 0.685 AC: 28403 AN: 41472

American (AMR) AF: 0.248 AC: 3786 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3468

East Asian (EAS) AF: 0.293 AC: 1514 AN: 5170

South Asian (SAS) AF: 0.177 AC: 854 AN: 4818

European-Finnish (FIN) AF: 0.226 AC: 2389 AN: 10558

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18094 AN: 67960

Other (OTH) AF: 0.362 AC: 765 AN: 2116

Alfa AF: 0.330 Hom.: 1252

Bravo AF: 0.397

Asia WGS AF: 0.270 AC: 937 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.9
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: rs1220134; hg19: chr2-158603556;