rs387906589

Variant names:

• chr2-157766004-C-A
• rs387906589
• NM_001111067.4:c.983G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-157766004-C-A
• chr2-157766004-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001111067.4(ACVR1):​c.983G>T​(p.Gly328Val) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G328W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Other O:3
• Conservation: PhyloP100: 7.88
• Publications: 97 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: G2P, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-157766005-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29594.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	NM_001111067.4	MANE Select	c.983G>T	p.Gly328Val	missense	Exon 8 of 11	NP_001104537.1	D3DPA4
	ACVR1	NM_001105.5		c.983G>T	p.Gly328Val	missense	Exon 8 of 11	NP_001096.1	D3DPA4
	ACVR1	NM_001347663.1		c.983G>T	p.Gly328Val	missense	Exon 8 of 11	NP_001334592.1	Q04771

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.983G>T	p.Gly328Val	missense	Exon 8 of 11	ENSP00000405004.1	Q04771
	ACVR1	ENST00000263640.7	TSL:1	c.983G>T	p.Gly328Val	missense	Exon 8 of 11	ENSP00000263640.3	Q04771
	ACVR1	ENST00000410057.6	TSL:1	c.983G>T	p.Gly328Val	missense	Exon 9 of 12	ENSP00000387127.2	Q04771

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Diffuse midline glioma, H3 K27M-mutant (2)
-	-	-	Embryonal rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.74		Gain of methylation at K329 (P = 0.041)
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.79
Mutation Taster		=4/96	disease causing

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: rs387906589; hg19: chr2-158622516; COSMIC: COSV55115998;