rs12997

Variant names:

• chr2-157736845-A-G
• rs12997
• NM_001111067.4:c.*686T>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.*686T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 336,656 control chromosomes in the GnomAD database, including 28,947 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 0.44 (19264 hom., cov: 33)
  • Exomes 𝑓: 0.30 (9683 hom.)
• Consequence: ACVR1 NM_001111067.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13
• Publications: 18 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.*686T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.*686T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_001111067.4	ENSP00000405004.1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66210 AN: 152040 Hom.: 19203 Cov.: 33

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.411

GnomAD4 exome AF: 0.304 AC: 56154 AN: 184498 Hom.: 9683 Cov.: 0 AF XY: 0.300 AC XY: 26819 AN XY: 89472

African (AFR) AF: 0.833 AC: 5066 AN: 6078

American (AMR) AF: 0.255 AC: 1329 AN: 5208

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 2657 AN: 7624

East Asian (EAS) AF: 0.271 AC: 5536 AN: 20392

South Asian (SAS) AF: 0.195 AC: 462 AN: 2366

European-Finnish (FIN) AF: 0.242 AC: 3351 AN: 13856

Middle Eastern (MID) AF: 0.330 AC: 330 AN: 1000

European-Non Finnish (NFE) AF: 0.287 AC: 33079 AN: 115202

Other (OTH) AF: 0.340 AC: 4344 AN: 12772

GnomAD4 genome AF: 0.436 AC: 66334 AN: 152158 Hom.: 19264 Cov.: 33 AF XY: 0.426 AC XY: 31700 AN XY: 74402

African (AFR) AF: 0.839 AC: 34827 AN: 41512

American (AMR) AF: 0.287 AC: 4388 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1233 AN: 3466

East Asian (EAS) AF: 0.322 AC: 1666 AN: 5174

South Asian (SAS) AF: 0.201 AC: 968 AN: 4824

European-Finnish (FIN) AF: 0.229 AC: 2426 AN: 10586

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19603 AN: 67992

Other (OTH) AF: 0.413 AC: 873 AN: 2112

Alfa AF: 0.319 Hom.: 10049

Bravo AF: 0.463

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myositis ossificans Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.014
DANN	Benign	0.45
PhyloP100		-1.1
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: rs12997; hg19: chr2-158593357; COSMIC: COSV55123946; COSMIC: COSV55123946;