rs1438073

Variant names:

• chr2-182264418-T-C
• rs1438073
• NM_001363871.4:c.54-4A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001363871.4(PDE1A):​c.54-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,607,678 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (9 hom.)
• Consequence: PDE1A NM_001363871.4 splice_region, intron
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363871.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE1A	NM_001363871.4	MANE Select	c.54-4A>G		splice_region intron	N/A	NP_001350800.1
	PDE1A	NM_001258312.3		c.114-4A>G		splice_region intron	N/A	NP_001245241.1
	PDE1A	NM_001395258.2		c.102-4A>G		splice_region intron	N/A	NP_001382187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE1A	ENST00000409365.6	TSL:5 MANE Select	c.54-4A>G		splice_region intron	N/A	ENSP00000386767.1
	PDE1A	ENST00000435564.6	TSL:1	c.102-4A>G		splice_region intron	N/A	ENSP00000410309.1
	PDE1A	ENST00000410103.2	TSL:1	c.102-4A>G		splice_region intron	N/A	ENSP00000387037.1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00105 AC: 261 AN: 248008 AF XY: 0.000799

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000623

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000394 AC: 574 AN: 1455532 Hom.: 9 Cov.: 27 AF XY: 0.000341 AC XY: 247 AN XY: 724428

African (AFR) AF: 0.0141 AC: 467 AN: 33214

American (AMR) AF: 0.000727 AC: 32 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107614

Other (OTH) AF: 0.00108 AC: 65 AN: 60108

GnomAD4 genome AF: 0.00408 AC: 620 AN: 152146 Hom.: 2 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74358

African (AFR) AF: 0.0139 AC: 578 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Benign	0.83
PhyloP100		1.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: -1

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

Other links and lift over

dbSNP: rs1438073; hg19: chr2-183129145;