rs2165436

Variant names:

• chr2-157870384-A-G
• rs2165436
• NM_001111067.4:c.-183+5412T>C

Variant summary

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

The NM_001111067.4(ACVR1):​c.-183+5412T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 152,096 control chromosomes in the GnomAD database, including 39,666 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 0.68 (39666 hom., cov: 32)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.732
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.-183+5412T>C		intron_variant	Intron 1 of 10	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.-183+5412T>C		intron_variant	Intron 1 of 10	1	NM_001111067.4	ENSP00000405004.1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103693 AN: 151978 Hom.: 39673 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.718

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

GnomAD4 genome AF: 0.682 AC: 103692 AN: 152096 Hom.: 39666 Cov.: 32 AF XY: 0.683 AC XY: 50797 AN XY: 74342

African (AFR) AF: 0.308 AC: 12765 AN: 41462

American (AMR) AF: 0.810 AC: 12388 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2684 AN: 3468

East Asian (EAS) AF: 0.613 AC: 3170 AN: 5172

South Asian (SAS) AF: 0.709 AC: 3416 AN: 4816

European-Finnish (FIN) AF: 0.849 AC: 8977 AN: 10576

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57825 AN: 67996

Other (OTH) AF: 0.713 AC: 1506 AN: 2112

Alfa AF: 0.733 Hom.: 5757

Bravo AF: 0.661

Asia WGS AF: 0.623 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.1
DANN	Benign	0.59
PhyloP100		0.73
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: rs2165436; hg19: chr2-158726896;