rs13406336

Positions:

• chr2-157799450-G-C

Variant summary

Our verdict is Benign. Variant got -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.29

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 -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	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	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.: 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

GnomAD3 exomes AF: 0.0104 AC: 2610 AN: 251244 Hom.: 50 AF XY: 0.0125 AC XY: 1696 AN XY: 135764

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.: 31 AF XY: 0.00992 AC XY: 7209 AN XY: 726428

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.: 9 Cov.: 32 AF XY: 0.00708 AC XY: 524 AN XY: 74044

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.: 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

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
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	D
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	T
MutationAssessor	Benign	0.55	N;N;N;N;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs13406336; hg19: chr2-158655962;