rs1146031

Positions:

• chr2-157770468-C-G
• chr2-157770468-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000434821.7(ACVR1):​c.690G>C​(p.Glu230Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E230G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ACVR1 ENST00000434821.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.982

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.690G>C	p.Glu230Asp	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.690G>C	p.Glu230Asp	missense_variant	7/11	1	NM_001111067.4	ENSP00000405004	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;D;D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;.;D;.
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.99	L;L;L;L
MutationTaster	Benign	1.5e-7	P;P;P;P
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.77	P;P;P;P
Vest4		0.80
MutPred		0.58		Loss of MoRF binding (P = 0.1314);Loss of MoRF binding (P = 0.1314);Loss of MoRF binding (P = 0.1314);Loss of MoRF binding (P = 0.1314);
MVP		0.84
MPC		1.6
ClinPred		0.95	D
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.86

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: rs1146031; hg19: chr2-158626980;