rs387906588

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

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

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.88

Publications

36 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

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ACMG classification

Classification was made for transcript

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 ClinVar as [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 ClinVar 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
ACVR1NM_001111067.4 linkc.982G>T p.Gly328Trp missense_variant Exon 8 of 11 ENST00000434821.7 NP_001104537.1 Q04771D3DPA4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACVR1ENST00000434821.7 linkc.982G>T p.Gly328Trp missense_variant Exon 8 of 11 1 NM_001111067.4 ENSP00000405004.1 Q04771

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
LINK: link

Submissions by phenotype

Progressive myositis ossificans Pathogenic:1
Mar 01, 2009
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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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

Publications

Other links and lift over

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