chr12-20369484-C-T

Variant names:

• chr12-20369484-C-T
• rs1179343639
• NM_000921.5:c.200C>T

Variant summary

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

The NM_000921.5(PDE3A):​c.200C>T​(p.Ala67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,658 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDE3A NM_000921.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.897

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=0.2184492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE3A	NM_000921.5	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 16	ENST00000359062.4	NP_000912.3
PDE3A	NM_001378407.1	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 14		NP_001365336.1
PDE3A	NM_001378408.1	c.-829C>T		5_prime_UTR_variant	Exon 1 of 18		NP_001365337.1
PDE3A-AS1	NR_186033.1	n.416+357G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE3A	ENST00000359062.4	c.200C>T	p.Ala67Val	missense_variant	Exon 1 of 16	1	NM_000921.5	ENSP00000351957.3
PDE3A-AS1	ENST00000535755.1	n.422+357G>A		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1404658 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 693600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 67 of the PDE3A protein (p.Ala67Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 1933394). 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. 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	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.95	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.10
Sift	Benign	0.096	T
Sift4G	Benign	0.12	T
Polyphen		0.64	P
Vest4		0.13
MutPred		0.29		Loss of disorder (P = 0.0846);
MVP		0.72
MPC		2.0
ClinPred		0.72	D
GERP RS		5.1
Varity_R		0.075
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1179343639; hg19: chr12-20522418;