12-20369318-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000921.5(PDE3A):c.34G>A(p.Asp12Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,544,406 control chromosomes in the GnomAD database, including 74,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (9574 hom., cov: 32)
  • Exomes 𝑓: 0.30 (64656 hom.)
• Consequence: PDE3A NM_000921.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.45

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5376678E-4).
• BP6: Variant 12-20369318-G-A is Benign according to our data. Variant chr12-20369318-G-A is described in ClinVar as [Benign]. Clinvar id is 1221712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE3A	NM_000921.5	c.34G>A	p.Asp12Asn	missense_variant	1/16	ENST00000359062.4
PDE3A	NM_001378407.1	c.34G>A	p.Asp12Asn	missense_variant	1/14
PDE3A	NM_001378408.1	c.-995G>A		5_prime_UTR_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE3A	ENST00000359062.4	c.34G>A	p.Asp12Asn	missense_variant	1/16	1	NM_000921.5	P1
PDE3A-AS1	ENST00000535755.1	n.422+523C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52207 AN: 151872 Hom.: 9567 Cov.: 32

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.287 AC: 40744 AN: 142038 Hom.: 6322 AF XY: 0.288 AC XY: 21920 AN XY: 76074

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.293

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.301 AC: 419779 AN: 1392416 Hom.: 64656 Cov.: 35 AF XY: 0.300 AC XY: 206105 AN XY: 686078

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.288

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.344 AC: 52233 AN: 151990 Hom.: 9574 Cov.: 32 AF XY: 0.343 AC XY: 25444 AN XY: 74288

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.336

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.310

Alfa AF: 0.301 Hom.: 14735

Bravo AF: 0.338

TwinsUK AF: 0.291 AC: 1079

ALSPAC AF: 0.315 AC: 1215

ESP6500AA AF: 0.416 AC: 1554

ESP6500EA AF: 0.269 AC: 1943

ExAC AF: 0.174 AC: 10458

Asia WGS AF: 0.291 AC: 1017 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.00025	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.42	T
Polyphen		0.079	B
Vest4		0.083
MPC		0.85
ClinPred		0.019	T
GERP RS		3.9
Varity_R		0.080
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12305038; hg19: chr12-20522252; COSMIC: COSV62969257; COSMIC: COSV62969257;