4-119502602-T-A

Position:

• chr4-119502602-T-A

Variant summary

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

The NM_001083.4(PDE5A):​c.2385A>T​(p.Lys795Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 0.166

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]

PDE5A (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=0.2787656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE5A	NM_001083.4	c.2385A>T	p.Lys795Asn	missense_variant	19/21	ENST00000354960.8	NP_001074.2
PDE5A	NM_033430.3	c.2259A>T	p.Lys753Asn	missense_variant	19/21		NP_236914.2
PDE5A	NM_033437.4	c.2229A>T	p.Lys743Asn	missense_variant	19/21		NP_246273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE5A	ENST00000354960.8	c.2385A>T	p.Lys795Asn	missense_variant	19/21	1	NM_001083.4	ENSP00000347046.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 21, 2024

The c.2385A>T (p.K795N) alteration is located in exon 19 (coding exon 19) of the PDE5A gene. This alteration results from a A to T substitution at nucleotide position 2385, causing the lysine (K) at amino acid position 795 to be replaced by an asparagine (N). 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	0.22
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.43	N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.27	B;.;B
Vest4		0.54
MutPred		0.46		Loss of ubiquitination at K795 (P = 0.0098);.;.;
MVP		0.70
MPC		0.45
ClinPred		0.49	T
GERP RS		0.60
Varity_R		0.45
gMVP		0.33

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: rs1725391933; hg19: chr4-120423757;