rs863224846

Positions:

• chr2-157770386-T-C
• chr2-157770386-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001111067.4(ACVR1):​c.772A>G​(p.Arg258Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.10

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain Protein kinase (size 294) in uniprot entity ACVR1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_001111067.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-157770384-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 2-157770386-T-C is Pathogenic according to our data. Variant chr2-157770386-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216885.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.772A>G	p.Arg258Gly	missense_variant	7/11	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.772A>G	p.Arg258Gly	missense_variant	7/11	1	NM_001111067.4	ENSP00000405004	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Progressive myositis ossificans Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Nov 27, 2012

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;.;D;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.76		Gain of catalytic residue at H259 (P = 0.0389);Gain of catalytic residue at H259 (P = 0.0389);Gain of catalytic residue at H259 (P = 0.0389);Gain of catalytic residue at H259 (P = 0.0389);
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.92

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: rs863224846; hg19: chr2-158626898; COSMIC: COSV55116294;