chr2-157766005-C-A

Variant names:

• chr2-157766005-C-A
• rs387906588
• NM_001111067.4:c.982G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001111067.4(ACVR1):​c.982G>T​(p.Gly328Trp) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G328V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.88
• Publications: 36 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-157766004-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 29595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 2-157766005-C-A is Pathogenic according to our data. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-157766005-C-A is described in CliVar as Pathogenic. Clinvar id is 29594.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.982G>T	p.Gly328Trp	missense_variant	Exon 8 of 11	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.982G>T	p.Gly328Trp	missense_variant	Exon 8 of 11	1	NM_001111067.4	ENSP00000405004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive myositis ossificans Pathogenic:1

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;M;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	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		0.79
MutPred		0.89		Loss of disorder (P = 0.0237);Loss of disorder (P = 0.0237);Loss of disorder (P = 0.0237);Loss of disorder (P = 0.0237);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs387906588; hg19: chr2-158622517; COSMIC: COSV55118965;