rs794726868

chr12-20616306-G-Achr12-20616306-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000921.5(PDE3A):c.1346G>A(p.Gly449Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G449V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE3A NM_000921.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 15) in uniprot entity PDE3A_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000921.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-20616306-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 193025.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 12-20616306-G-A is Pathogenic according to our data. Variant chr12-20616306-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 977321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-20616306-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE3A	NM_000921.5	c.1346G>A	p.Gly449Asp	missense_variant	4/16	ENST00000359062.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE3A	ENST00000359062.4	c.1346G>A	p.Gly449Asp	missense_variant	4/16	1	NM_000921.5	P1
PDE3A	ENST00000544307.1	n.643G>A		non_coding_transcript_exon_variant	3/15	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brachydactyly-arterial hypertension syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Jun 01, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly449 amino acid residue in PDE3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25961942). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 449 of the PDE3A protein (p.Gly449Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertension and brachydactyly syndrome (PMID: 29758562, 31549136, 32631253). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 977321). 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 disruptive. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.81
MPC		0.46
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.61

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

Other links and lift over

dbSNP: rs794726868; hg19: chr12-20769240;