chr2-157799450-G-C

Position:

chr2-157799450-G-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 257465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-157799450-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1020 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR1	NM_001111067.4 linkuse as main transcript	c.44C>G	p.Ala15Gly	missense_variant	3/11	ENST00000434821.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1	ENST00000434821.7 linkuse as main transcript	c.44C>G	p.Ala15Gly	missense_variant	3/11	1	NM_001111067.4	P4

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

GnomAD3 exomes

AF:

0.0104

AC:

2610

AN:

251244

Hom.:

AF XY:

0.0125

AC XY:

1696

AN XY:

135764

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 SAS exome

AF:

0.0416

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

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00362

Gnomad4 ASJ exome

AF:

0.00805

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0404

Gnomad4 FIN exome

AF:

0.00512

Gnomad4 NFE exome

AF:

0.00718

Gnomad4 OTH exome

AF:

0.00904

GnomAD4 genome

AF:

0.00673

AC:

1020

AN:

151558

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

524

AN XY:

74044

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00761

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0320

Gnomad4 FIN

AF:

0.00658

Gnomad4 NFE

AF:

0.00858

Gnomad4 OTH

AF:

0.00475

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ACVR1: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2015	- -

Progressive myositis ossificans

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

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;.;.;.;.;.

MutationTaster

Benign

0.91

D;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over