chr2-157799450-G-C

Variant names:

• chr2-157799450-G-C
• rs13406336
• NM_001111067.4:c.44C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111067.4(ACVR1):​c.44C>G​(p.Ala15Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00858 in 1,611,556 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (168 hom.)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.29
• Publications: 19 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: G2P, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.004531741).
• BP6: Variant 2-157799450-G-C is Benign according to our data. Variant chr2-157799450-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00673 (1020/151558) while in subpopulation SAS AF = 0.032 (153/4782). AF 95% confidence interval is 0.0279. There are 9 homozygotes in GnomAd4. There are 524 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1020 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	NM_001111067.4	MANE Select	c.44C>G	p.Ala15Gly	missense	Exon 3 of 11	NP_001104537.1	D3DPA4
	ACVR1	NM_001105.5		c.44C>G	p.Ala15Gly	missense	Exon 3 of 11	NP_001096.1	D3DPA4
	ACVR1	NM_001347663.1		c.44C>G	p.Ala15Gly	missense	Exon 3 of 11	NP_001334592.1	Q04771

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.44C>G	p.Ala15Gly	missense	Exon 3 of 11	ENSP00000405004.1	Q04771
	ACVR1	ENST00000263640.7	TSL:1	c.44C>G	p.Ala15Gly	missense	Exon 3 of 11	ENSP00000263640.3	Q04771
	ACVR1	ENST00000410057.6	TSL:1	c.44C>G	p.Ala15Gly	missense	Exon 4 of 12	ENSP00000387127.2	Q04771

Frequencies

GnomAD3 genomes AF: 0.00673 AC: 1019 AN: 151476 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00762

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.00658

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.0104 AC: 2610 AN: 251244 AF XY: 0.0125

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.00850

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.00877 AC: 12803 AN: 1459998 Hom.: 168 Cov.: 31 AF XY: 0.00992 AC XY: 7209 AN XY: 726428

African (AFR) AF: 0.00105 AC: 35 AN: 33424

American (AMR) AF: 0.00362 AC: 162 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00805 AC: 210 AN: 26084

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39594

South Asian (SAS) AF: 0.0404 AC: 3486 AN: 86186

European-Finnish (FIN) AF: 0.00512 AC: 273 AN: 53360

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5760

European-Non Finnish (NFE) AF: 0.00718 AC: 7969 AN: 1110578

Other (OTH) AF: 0.00904 AC: 545 AN: 60300

GnomAD4 genome AF: 0.00673 AC: 1020 AN: 151558 Hom.: 9 Cov.: 32 AF XY: 0.00708 AC XY: 524 AN XY: 74044

African (AFR) AF: 0.00140 AC: 58 AN: 41352

American (AMR) AF: 0.00761 AC: 116 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5146

South Asian (SAS) AF: 0.0320 AC: 153 AN: 4782

European-Finnish (FIN) AF: 0.00658 AC: 68 AN: 10338

Middle Eastern (MID) AF: 0.0345 AC: 10 AN: 290

European-Non Finnish (NFE) AF: 0.00858 AC: 583 AN: 67928

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00801 Hom.: 1

Bravo AF: 0.00537

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.0110 AC: 1331

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00942

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Progressive myositis ossificans (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.25
Sift	Uncertain	0.019	D
Sift4G	Benign	0.13	T
Polyphen		0.016	B
Vest4		0.15
MPC		0.69
ClinPred		0.010	T
GERP RS		5.8
Varity_R		0.067
gMVP		0.38
Mutation Taster		=98/2	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: rs13406336; hg19: chr2-158655962;