chr12-20369330-C-T

Variant names:

• chr12-20369330-C-T
• rs754034584
• NM_000921.5:c.46C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000921.5(PDE3A):​c.46C>T​(p.His16Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,547,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000050 (0 hom.)
• Consequence: PDE3A NM_000921.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0710
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05262384).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000921.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE3A	NM_000921.5	MANE Select	c.46C>T	p.His16Tyr	missense	Exon 1 of 16	NP_000912.3
	PDE3A	NM_001378407.1		c.46C>T	p.His16Tyr	missense	Exon 1 of 14	NP_001365336.1
	PDE3A	NM_001378408.1		c.-983C>T		5_prime_UTR	Exon 1 of 18	NP_001365337.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE3A	ENST00000359062.4	TSL:1 MANE Select	c.46C>T	p.His16Tyr	missense	Exon 1 of 16	ENSP00000351957.3	Q14432
	PDE3A	ENST00000951762.1		c.46C>T	p.His16Tyr	missense	Exon 1 of 15	ENSP00000621821.1
	PDE3A-AS1	ENST00000535755.1	TSL:4	n.422+511G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000348 AC: 5 AN: 143758 AF XY: 0.0000389

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000502 AC: 7 AN: 1395178 Hom.: 0 Cov.: 34 AF XY: 0.00000582 AC XY: 4 AN XY: 687818

African (AFR) AF: 0.00 AC: 0 AN: 31510

American (AMR) AF: 0.000141 AC: 5 AN: 35560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.00 AC: 0 AN: 78946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077556

Other (OTH) AF: 0.0000173 AC: 1 AN: 57804

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000260 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.6
DANN	Benign	0.82
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.071
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.18
Sift	Uncertain	0.025	D
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.14		Gain of phosphorylation at H16 (P = 0.0137)
MVP		0.27
MPC		0.99
ClinPred		0.068	T
GERP RS		-0.37
Varity_R		0.079
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754034584; hg19: chr12-20522264;