rs12327948

Variant names:

• chr2-157812905-G-C
• rs12327948
• NM_001111067.4:c.-8+5480C>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+5480C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 152,016 control chromosomes in the GnomAD database, including 39,966 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 (39966 hom., cov: 32)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.837 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.-8+5480C>G		intron	N/A	NP_001104537.1
	ACVR1	NM_001105.5		c.-8+5480C>G		intron	N/A	NP_001096.1
	ACVR1	NM_001347663.1		c.-8+5480C>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.-8+5480C>G		intron	N/A	ENSP00000405004.1
	ACVR1	ENST00000263640.7	TSL:1	c.-8+5480C>G		intron	N/A	ENSP00000263640.3
	ACVR1	ENST00000410057.6	TSL:1	c.-8+5480C>G		intron	N/A	ENSP00000387127.2

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103541 AN: 151898 Hom.: 39958 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.724

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

GnomAD4 genome AF: 0.681 AC: 103573 AN: 152016 Hom.: 39966 Cov.: 32 AF XY: 0.687 AC XY: 51009 AN XY: 74288

African (AFR) AF: 0.281 AC: 11651 AN: 41426

American (AMR) AF: 0.804 AC: 12271 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 3029 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4119 AN: 5180

South Asian (SAS) AF: 0.859 AC: 4142 AN: 4820

European-Finnish (FIN) AF: 0.841 AC: 8875 AN: 10558

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 56990 AN: 67980

Other (OTH) AF: 0.725 AC: 1528 AN: 2108

Alfa AF: 0.746 Hom.: 5665

Bravo AF: 0.655

Asia WGS AF: 0.785 AC: 2722 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.39
PhyloP100		0.14
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: rs12327948; hg19: chr2-158669417;