4-119525571-T-C

Variant summary

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

The NM_001083.4(PDE5A):c.1757A>G(p.Gln586Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.1757A>G	p.Gln586Arg	missense_variant	12/21	ENST00000354960.8
PDE5A	NM_033430.3	c.1631A>G	p.Gln544Arg	missense_variant	12/21
PDE5A	NM_033437.4	c.1601A>G	p.Gln534Arg	missense_variant	12/21
PDE5A	XM_017008791.3	c.1757A>G	p.Gln586Arg	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8	c.1757A>G	p.Gln586Arg	missense_variant	12/21	1	NM_001083.4
	ENST00000688315.1	n.1276-3169T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 13, 2022

The c.1757A>G (p.Q586R) alteration is located in exon 12 (coding exon 12) of the PDE5A gene. This alteration results from a A to G substitution at nucleotide position 1757, causing the glutamine (Q) at amino acid position 586 to be replaced by an arginine (R). 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	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.090	B;.;B
Vest4		0.79
MutPred		0.46		Gain of MoRF binding (P = 0.0353);.;.;
MVP		0.64
MPC		1.1
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.79
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-120446726;