NM_001616.5:c.1303A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001616.5(ACVR2A):c.1303A>C(p.Lys435Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACVR2A
NM_001616.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38715684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2A	NM_001616.5 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 10 of 11	ENST00000241416.12	NP_001607.1	P27037-1
ACVR2A	NM_001278579.2 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 11 of 12		NP_001265508.1	P27037-1
ACVR2A	NM_001278580.2 link	c.979A>C	p.Lys327Gln	missense_variant	Exon 10 of 11		NP_001265509.1	P27037-2
ACVR2A	XM_047446292.1 link	c.979A>C	p.Lys327Gln	missense_variant	Exon 10 of 11		XP_047302248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR2A	ENST00000241416.12 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 10 of 11	1	NM_001616.5	ENSP00000241416.7	P27037-1
ACVR2A	ENST00000404590.1 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 11 of 12	1		ENSP00000384338.1	P27037-1
ACVR2A	ENST00000535787.5 link	c.979A>C	p.Lys327Gln	missense_variant	Exon 10 of 11	2		ENSP00000439988.1	P27037-2
ACVR2A	ENST00000495775.1 link	n.431A>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246654

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1303A>C (p.K435Q) alteration is located in exon 10 (coding exon 10) of the ACVR2A gene. This alteration results from a A to C substitution at nucleotide position 1303, causing the lysine (K) at amino acid position 435 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

Benign

0.16

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.038

D;T;D

Sift4G

Benign

0.10

T;T;T

Polyphen

0.81

P;.;P

Vest4

0.52

MutPred

0.46

Loss of methylation at K435 (P = 0.018);.;Loss of methylation at K435 (P = 0.018);

MVP

0.74

MPC

1.5

ClinPred

0.89

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

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

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