rs12694937

chr2-157800921-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001111067.4(ACVR1):c.-7-1421A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 151,894 control chromosomes in the GnomAD database, including 669 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 0.065 (669 hom., cov: 31)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR1	NM_001111067.4	c.-7-1421A>G		intron_variant		ENST00000434821.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1	ENST00000434821.7	c.-7-1421A>G		intron_variant		1	NM_001111067.4	P4

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9912 AN: 151776 Hom.: 666 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0648

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

GnomAD4 genome AF: 0.0654 AC: 9933 AN: 151894 Hom.: 669 Cov.: 31 AF XY: 0.0627 AC XY: 4657 AN XY: 74238

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.0188

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0646

Alfa AF: 0.0335 Hom.: 163

Bravo AF: 0.0734

Asia WGS AF: 0.0260 AC: 91 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	12
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12694937; hg19: chr2-158657433;