2-157736845-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• 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, single submitter B:1
• Conservation: PhyloP100: -1.13

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 2-157736845-A-G is Benign according to our data. Variant chr2-157736845-A-G is described in ClinVar as [Benign]. Clinvar id is 331676.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
ACVR1	NM_001111067.4	c.*686T>C		3_prime_UTR_variant	11/11	ENST00000434821.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1	ENST00000434821.7	c.*686T>C		3_prime_UTR_variant	11/11	1	NM_001111067.4	P4

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

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.349

Gnomad4 EAS exome AF: 0.271

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.340

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

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.288

Gnomad4 OTH AF: 0.413

Alfa AF: 0.312 Hom.: 8409

Bravo AF: 0.463

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myositis ossificans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.014
Dann	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs12997; hg19: chr2-158593357; COSMIC: COSV55123946; COSMIC: COSV55123946;