2-157799450-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.29

Publications

19 publications found

Variant links:

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

ACVR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4 link	c.44C>G	p.Ala15Gly	missense_variant	Exon 3 of 11	ENST00000434821.7	NP_001104537.1	Q04771D3DPA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7 link	c.44C>G	p.Ala15Gly	missense_variant	Exon 3 of 11	1	NM_001111067.4	ENSP00000405004.1		Q04771

Frequencies

GnomAD3 genomes

AF:

0.00673

AC:

1019

AN:

151476

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00992

AC XY:

7209

AN XY:

726428

show subpopulations

African (AFR)

AF:

0.00105

AC:

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

536

1072

1608

2144

2680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00673

AC:

1020

AN:

151558

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

524

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41352

American (AMR)

AF:

0.00761

AC:

116

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5146

South Asian (SAS)

AF:

0.0320

AC:

153

AN:

4782

European-Finnish (FIN)

AF:

0.00658

AC:

AN:

10338

Middle Eastern (MID)

AF:

0.0345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00858

AC:

583

AN:

67928

Other (OTH)

AF:

0.00475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00801

Hom.:

Bravo

AF:

0.00537

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.0110

AC:

1331

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00942

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACVR1: BS1, BS2 -

Nov 25, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:2

Dec 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive myositis ossificans

Benign:2

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;T;T;.;T;.;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.72

.;.;T;.;T;T;T;T;T

MetaRNN

Benign

0.0045

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.083

MutationAssessor

Benign

0.55

N;N;N;N;.;.;.;.;.

PhyloP100

4.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.77

N;N;N;N;N;N;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.019

D;D;D;D;T;T;D;D;.

Sift4G

Benign

0.13

T;T;T;T;.;.;.;.;.

Polyphen

0.016

B;B;B;B;.;.;.;.;.

Vest4

0.15

MPC

0.69

ClinPred

0.010

GERP RS

5.8

Varity_R

0.067

gMVP

0.38

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over