chr12-20369453-A-G

Variant names:

• chr12-20369453-A-G
• NM_000921.5:c.169A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000921.5(PDE3A):​c.169A>G​(p.Ser57Gly) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE3A NM_000921.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.482

Genes affected

PDE3A (HGNC:8778): (phosphodiesterase 3A) This gene encodes a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase (cGI-PDE) family. cGI-PDE enzymes hydrolyze both cAMP and cGMP, and play critical roles in many cellular processes by regulating the amplitude and duration of intracellular cyclic nucleotide signals. The encoded protein mediates platelet aggregation and also plays important roles in cardiovascular function by regulating vascular smooth muscle contraction and relaxation. Inhibitors of the encoded protein may be effective in treating congestive heart failure. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

PDE3A-AS1 (HGNC:40436): (PDE3A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10405409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE3A	NM_000921.5	c.169A>G	p.Ser57Gly	missense_variant	Exon 1 of 16	ENST00000359062.4	NP_000912.3
PDE3A	NM_001378407.1	c.169A>G	p.Ser57Gly	missense_variant	Exon 1 of 14		NP_001365336.1
PDE3A	NM_001378408.1	c.-860A>G		5_prime_UTR_variant	Exon 1 of 18		NP_001365337.1
PDE3A-AS1	NR_186033.1	n.416+388T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE3A	ENST00000359062.4	c.169A>G	p.Ser57Gly	missense_variant	Exon 1 of 16	1	NM_000921.5	ENSP00000351957.3
PDE3A-AS1	ENST00000535755.1	n.422+388T>C		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169A>G (p.S57G) alteration is located in exon 1 (coding exon 1) of the PDE3A gene. This alteration results from a A to G substitution at nucleotide position 169, causing the serine (S) at amino acid position 57 to be replaced by a glycine (G). 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	0.052
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.22	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.17
Sift	Benign	0.085	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.048
MutPred		0.13		Loss of phosphorylation at S57 (P = 0.0255);
MVP		0.51
MPC		0.79
ClinPred		0.26	T
GERP RS		1.7
Varity_R		0.084
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-20522387;