21-42743784-C-A

Variant summary

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

The NM_002606.3(PDE9A):c.577C>A(p.Leu193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,206 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L193P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PDE9A NM_002606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

PDE9A (HGNC:8795): (phosphodiesterase 9A) The protein encoded by this gene catalyzes the hydrolysis of cAMP and cGMP to their corresponding monophosphates. The encoded protein plays a role in signal transduction by regulating the intracellular concentration of these cyclic nucleotides. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.22272846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE9A	NM_002606.3	c.577C>A	p.Leu193Ile	missense_variant	8/20	ENST00000291539.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE9A	ENST00000291539.11	c.577C>A	p.Leu193Ile	missense_variant	8/20	1	NM_002606.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000461 AC: 1 AN: 216732 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 116568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435206 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 712284

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.577C>A (p.L193I) alteration is located in exon 8 (coding exon 8) of the PDE9A gene. This alteration results from a C to A substitution at nucleotide position 577, causing the leucine (L) at amino acid position 193 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.71	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.36	B;B;B;P;B;P;B;P;D;B;P;P;P
Vest4		0.39
MutPred		0.31		.;Gain of methylation at K194 (P = 0.0432);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.70
MPC		0.82
ClinPred		0.68	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.58

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: rs982358967; hg19: chr21-44163894;