Genetic Variant PDE3A:c.-77_-74dupTGTG (chr12-20369190-C-CGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000921.5(PDE3A):c.-77_-74dupTGTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 653,624 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

PDE3A
NM_000921.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.115

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 35 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PDE3A	NM_000921.5	MANE Select	c.-77_-74dupTGTG	5_prime_UTR	Exon 1 of 16	NP_000912.3
PDE3A	NM_001378407.1		c.-77_-74dupTGTG	5_prime_UTR	Exon 1 of 14	NP_001365336.1
PDE3A	NM_001378408.1		c.-1105_-1102dupTGTG	5_prime_UTR	Exon 1 of 18	NP_001365337.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE3A	ENST00000359062.4	TSL:1 MANE Select	c.-77_-74dupTGTG	5_prime_UTR	Exon 1 of 16	ENSP00000351957.3	Q14432
PDE3A	ENST00000951762.1		c.-77_-74dupTGTG	5_prime_UTR	Exon 1 of 15	ENSP00000621821.1
PDE3A-AS1	ENST00000535755.1	TSL:4	n.422+647_422+650dupACAC	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000240

AC:

AN:

145556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000273

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000218

Gnomad SAS

AF:

0.000221

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000288

Gnomad OTH

AF:

0.000505

GnomAD4 exome

AF:

0.000272

AC:

138

AN:

507960

Hom.:

AF XY:

0.000327

AC XY:

AN XY:

260132

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000317

AC:

AN:

12624

American (AMR)

AF:

0.000183

AC:

AN:

16354

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

12868

East Asian (EAS)

AF:

0.0000362

AC:

AN:

27642

South Asian (SAS)

AF:

0.000570

AC:

AN:

38620

European-Finnish (FIN)

AF:

0.000259

AC:

AN:

30852

Middle Eastern (MID)

AF:

0.000955

AC:

AN:

2094

European-Non Finnish (NFE)

AF:

0.000259

AC:

AN:

339920

Other (OTH)

AF:

0.000296

AC:

AN:

26986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000240

AC:

AN:

145664

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

70874

show subpopulations

African (AFR)

AF:

0.000226

AC:

AN:

39894

American (AMR)

AF:

0.000273

AC:

AN:

14654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.000219

AC:

AN:

4570

South Asian (SAS)

AF:

0.000221

AC:

AN:

4524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000288

AC:

AN:

66042

Other (OTH)

AF:

0.000500

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000140

Hom.:

293

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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12-20369190-CGTGTGTGTGTGT-CGTGTGTGTGTGTGTGT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over