4-119505929-C-A

Variant names:

• chr4-119505929-C-A
• NM_001083.4:c.2193G>T

Variant summary

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

The NM_001083.4(PDE5A):​c.2193G>T​(p.Arg731Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160

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]

ENSG00000291203 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE5A	NM_001083.4	c.2193G>T	p.Arg731Ser	missense_variant	Exon 17 of 21	ENST00000354960.8	NP_001074.2
PDE5A	NM_033430.3	c.2067G>T	p.Arg689Ser	missense_variant	Exon 17 of 21		NP_236914.2
PDE5A	NM_033437.4	c.2037G>T	p.Arg679Ser	missense_variant	Exon 17 of 21		NP_246273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE5A	ENST00000354960.8	c.2193G>T	p.Arg731Ser	missense_variant	Exon 17 of 21	1	NM_001083.4	ENSP00000347046.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2193G>T (p.R731S) alteration is located in exon 17 (coding exon 17) of the PDE5A gene. This alteration results from a G to T substitution at nucleotide position 2193, causing the arginine (R) at amino acid position 731 to be replaced by a serine (S). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;D;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.69	P;.;P
Vest4		0.67
MutPred		0.71		Gain of ubiquitination at K730 (P = 0.0554);.;.;
MVP		0.77
MPC		0.94
ClinPred		0.79	D
GERP RS		-4.5
Varity_R		0.87
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-120427084;