Genetic Variant PDE1A:c.1516+17596_1516+17598delTTT (chr2-182168293-GAAA-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001003683.3(PDE1A):c.1565-6_1565-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,177,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PDE1A
NM_001003683.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.659

Publications

1 publications found

Variant links:

Genes affected

PDE1A (HGNC:8774): (phosphodiesterase 1A) Cyclic nucleotide phosphodiesterases (PDEs) play a role in signal transduction by regulating intracellular cyclic nucleotide concentrations through hydrolysis of cAMP and/or cGMP to their respective nucleoside 5-prime monophosphates. Members of the PDE1 family, such as PDE1A, are Ca(2+)/calmodulin (see CALM1; MIM 114180)-dependent PDEs (CaM-PDEs) that are activated by calmodulin in the presence of Ca(2+) (Michibata et al., 2001 [PubMed 11342109]; Fidock et al., 2002 [PubMed 11747989]).[supplied by OMIM, Oct 2009]

PDE1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003683.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE1A	NM_001363871.4	MANE Select	c.1516+17596_1516+17598delTTT	intron	N/A	NP_001350800.1	P54750-6
PDE1A	NM_001258312.3		c.1576+17596_1576+17598delTTT	intron	N/A	NP_001245241.1
PDE1A	NM_001395258.2		c.1564+17596_1564+17598delTTT	intron	N/A	NP_001382187.1	P54750-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE1A	ENST00000409365.6	TSL:5 MANE Select	c.1516+17596_1516+17598delTTT	intron	N/A	ENSP00000386767.1	P54750-6
PDE1A	ENST00000435564.6	TSL:1	c.1564+17596_1564+17598delTTT	intron	N/A	ENSP00000410309.1	P54750-4
PDE1A	ENST00000410103.2	TSL:1	c.1565-6_1565-4delTTT	splice_region intron	N/A	ENSP00000387037.1	P54750-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

135886

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000348

AC:

AN:

114962

AF XY:

0.0000319

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000212

AC:

AN:

1177714

Hom.:

AF XY:

0.0000239

AC XY:

AN XY:

585760

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25834

American (AMR)

AF:

0.000213

AC:

AN:

28112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20316

East Asian (EAS)

AF:

0.00

AC:

AN:

32968

South Asian (SAS)

AF:

0.0000311

AC:

AN:

64366

European-Finnish (FIN)

AF:

0.0000238

AC:

AN:

42100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4594

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

911034

Other (OTH)

AF:

0.0000620

AC:

AN:

48390

⚠️ 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: 0.239

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

135946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65448

African (AFR)

AF:

0.00

AC:

AN:

37208

American (AMR)

AF:

0.00

AC:

AN:

13840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3210

East Asian (EAS)

AF:

0.00

AC:

AN:

4832

South Asian (SAS)

AF:

0.00

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62140

Other (OTH)

AF:

0.00

AC:

AN:

1852

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.66

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over