NM_001111067.4:c.543+1232T>G

Variant names:

• chr2-157776899-A-C
• rs1146035
• NM_001111067.4:c.543+1232T>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.543+1232T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 152,296 control chromosomes in the GnomAD database, including 52,020 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 0.83 (52020 hom., cov: 33)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.350
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 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.543+1232T>G		intron	N/A	NP_001104537.1
	ACVR1	NM_001105.5		c.543+1232T>G		intron	N/A	NP_001096.1
	ACVR1	NM_001347663.1		c.543+1232T>G		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.543+1232T>G		intron	N/A	ENSP00000405004.1
	ACVR1	ENST00000263640.7	TSL:1	c.543+1232T>G		intron	N/A	ENSP00000263640.3
	ACVR1	ENST00000410057.6	TSL:1	c.543+1232T>G		intron	N/A	ENSP00000387127.2

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125709 AN: 152178 Hom.: 51969 Cov.: 33

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.826

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

GnomAD4 genome AF: 0.826 AC: 125819 AN: 152296 Hom.: 52020 Cov.: 33 AF XY: 0.829 AC XY: 61715 AN XY: 74452

African (AFR) AF: 0.800 AC: 33257 AN: 41562

American (AMR) AF: 0.851 AC: 13019 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2972 AN: 3470

East Asian (EAS) AF: 0.930 AC: 4828 AN: 5194

South Asian (SAS) AF: 0.860 AC: 4149 AN: 4826

European-Finnish (FIN) AF: 0.851 AC: 9022 AN: 10602

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55861 AN: 68024

Other (OTH) AF: 0.827 AC: 1749 AN: 2114

Alfa AF: 0.820 Hom.: 20145

Bravo AF: 0.820

Asia WGS AF: 0.900 AC: 3127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.8
DANN	Benign	0.66
PhyloP100		-0.35
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: rs1146035; hg19: chr2-158633411;