12-20369289-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000921.5(PDE3A):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000099 in 1,515,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000095 ( 0 hom. )

Consequence

PDE3A
NM_000921.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

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 links:

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

PDE3A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20449865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDE3A	NM_000921.5 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/16	ENST00000359062.4
PDE3A	NM_001378407.1 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/14
PDE3A	NM_001378408.1 linkuse as main transcript	c.-1024C>T		5_prime_UTR_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE3A	ENST00000359062.4 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/16	1	NM_000921.5	P1
PDE3A-AS1	ENST00000535755.1 linkuse as main transcript	n.422+552G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

123168

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000454

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000954

AC:

AN:

1363392

Hom.:

Cov.:

AF XY:

0.00000599

AC XY:

AN XY:

667552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000755

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74204

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the PDE3A protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PDE3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1988732). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.58

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.66

REVEL

Benign

0.023

Sift

Benign

0.19

Sift4G

Pathogenic

0.0

Polyphen

0.0060

Vest4

0.19

MutPred

0.38

Loss of MoRF binding (P = 0.1316);

MVP

0.51

MPC

0.86

ClinPred

0.16

GERP RS

0.84

Varity_R

0.054

gMVP

0.67

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