4-119501172-C-G

Variant names:

• chr4-119501172-C-G
• rs199573045
• NM_001083.4:c.2488G>C

Variant summary

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

The NM_001083.4(PDE5A):​c.2488G>C​(p.Glu830Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000546 in 1,593,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense, splice_region
• Scores: Splicing: ADA: 0.2258
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35141933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE5A	NM_001083.4	c.2488G>C	p.Glu830Gln	missense_variant, splice_region_variant	Exon 20 of 21	ENST00000354960.8	NP_001074.2
PDE5A	NM_033430.3	c.2362G>C	p.Glu788Gln	missense_variant, splice_region_variant	Exon 20 of 21		NP_236914.2
PDE5A	NM_033437.4	c.2332G>C	p.Glu778Gln	missense_variant, splice_region_variant	Exon 20 of 21		NP_246273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE5A	ENST00000354960.8	c.2488G>C	p.Glu830Gln	missense_variant, splice_region_variant	Exon 20 of 21	1	NM_001083.4	ENSP00000347046.3

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250630 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135484

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000326 AC: 47 AN: 1440840 Hom.: 0 Cov.: 26 AF XY: 0.0000265 AC XY: 19 AN XY: 718318

Gnomad4 AFR exome AF: 0.00121

Gnomad4 AMR exome AF: 0.0000671

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: 9.15e-7

Gnomad4 OTH exome AF: 0.0000503

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74430

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

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.2488G>C (p.E830Q) alteration is located in exon 20 (coding exon 20) of the PDE5A gene. This alteration results from a G to C substitution at nucleotide position 2488, causing the glutamic acid (E) at amino acid position 830 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.76	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.41	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.024	B;.;B
Vest4		0.61
MVP		0.93
MPC		0.37
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.47
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.23
dbscSNV1_RF	Benign	0.41
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: rs199573045; hg19: chr4-120422327;