chr2-157736845-A-G

Variant names:

• chr2-157736845-A-G
• rs12997
• NM_001111067.4:c.*686T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. 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, 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 -20 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 VariationId is 331676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 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.*686T>C		3_prime_UTR	Exon 11 of 11	NP_001104537.1
	ACVR1	NM_001105.5		c.*686T>C		3_prime_UTR	Exon 11 of 11	NP_001096.1
	ACVR1	NM_001347663.1		c.*686T>C		3_prime_UTR	Exon 11 of 11	NP_001334592.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.*686T>C		3_prime_UTR	Exon 11 of 11	ENSP00000405004.1
	ACVR1	ENST00000263640.7	TSL:1	c.*686T>C		3_prime_UTR	Exon 11 of 11	ENSP00000263640.3
	ACVR1	ENST00000681995.1		n.1815T>C		non_coding_transcript_exon	Exon 3 of 3

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Progressive myositis ossificans (1)

Computational scores

Source: dbNSFP v4.9

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;