2-147922983-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001616.5(ACVR2A):c.1088G>A(p.Arg363Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACVR2A
NM_001616.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99

Variant links:

Genes affected

ACVR2A (HGNC:173): (activin A receptor type 2A) This gene encodes a receptor that mediates the functions of activins, which are members of the transforming growth factor-beta (TGF-beta) superfamily involved in diverse biological processes. The encoded protein is a transmembrane serine-threonine kinase receptor which mediates signaling by forming heterodimeric complexes with various combinations of type I and type II receptors and ligands in a cell-specific manner. The encoded type II receptor is primarily involved in ligand-binding and includes an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic serine-threonine kinase domain. This gene may be associated with susceptibility to preeclampsia, a pregnancy-related disease which can result in maternal and fetal morbidity and mortality. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jun 2013]

ACVR2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, ACVR2A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACVR2A	NM_001616.5 linkuse as main transcript	c.1088G>A	p.Arg363Gln	missense_variant	9/11	ENST00000241416.12
ACVR2A	NM_001278579.2 linkuse as main transcript	c.1088G>A	p.Arg363Gln	missense_variant	10/12
ACVR2A	NM_001278580.2 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	9/11
ACVR2A	XM_047446292.1 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2A	ENST00000241416.12 linkuse as main transcript	c.1088G>A	p.Arg363Gln	missense_variant	9/11	1	NM_001616.5	P1	P27037-1
ACVR2A	ENST00000404590.1 linkuse as main transcript	c.1088G>A	p.Arg363Gln	missense_variant	10/12	1		P1	P27037-1
ACVR2A	ENST00000535787.5 linkuse as main transcript	c.764G>A	p.Arg255Gln	missense_variant	9/11	2			P27037-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152026

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456092

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.1088G>A (p.R363Q) alteration is located in exon 9 (coding exon 9) of the ACVR2A gene. This alteration results from a G to A substitution at nucleotide position 1088, causing the arginine (R) at amino acid position 363 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.1

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.034

D;T;D

Polyphen

1.0

D;.;D

Vest4

0.57

MutPred

0.63

Loss of methylation at R363 (P = 0.032);.;Loss of methylation at R363 (P = 0.032);

MVP

0.95

MPC

2.0

ClinPred

0.99

GERP RS

5.7

Varity_R

0.94

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over