4-119521050-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001083.4(PDE5A):c.1790G>A(p.Arg597Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

Genes affected

PDE5A (HGNC:8784): (phosphodiesterase 5A) This gene encodes a cGMP-binding, cGMP-specific phosphodiesterase, a member of the cyclic nucleotide phosphodiesterase family. This phosphodiesterase specifically hydrolyzes cGMP to 5'-GMP. It is involved in the regulation of intracellular concentrations of cyclic nucleotides and is important for smooth muscle relaxation in the cardiovascular system. Alternative splicing of this gene results in three transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35677785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.1790G>A	p.Arg597Lys	missense_variant	13/21	ENST00000354960.8
PDE5A	NM_033430.3	c.1664G>A	p.Arg555Lys	missense_variant	13/21
PDE5A	NM_033437.4	c.1634G>A	p.Arg545Lys	missense_variant	13/21
PDE5A	XM_017008791.3	c.1790G>A	p.Arg597Lys	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8	c.1790G>A	p.Arg597Lys	missense_variant	13/21	1	NM_001083.4
	ENST00000688315.1	n.1276-7690C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458580 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725482

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000378

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

Nov 01, 2022

The c.1790G>A (p.R597K) alteration is located in exon 13 (coding exon 13) of the PDE5A gene. This alteration results from a G to A substitution at nucleotide position 1790, causing the arginine (R) at amino acid position 597 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;T;.
Eigen	Benign	0.094
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N;D;D
REVEL	Benign	0.25
Sift	Benign	0.089	T;D;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.0040	B;.;B
Vest4		0.23
MutPred		0.62		Gain of methylation at R597 (P = 0.0017);.;.;
MVP		0.73
MPC		0.32
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.56
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1726111452; hg19: chr4-120442205;