4-119520966-A-G

Variant names:

• chr4-119520966-A-G
• rs199872206
• NM_001083.4:c.1874T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001083.4(PDE5A):​c.1874T>C​(p.Met625Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,612,402 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (3 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE5A	NM_001083.4	c.1874T>C	p.Met625Thr	missense_variant	Exon 13 of 21	ENST00000354960.8	NP_001074.2
PDE5A	NM_033430.3	c.1748T>C	p.Met583Thr	missense_variant	Exon 13 of 21		NP_236914.2
PDE5A	NM_033437.4	c.1718T>C	p.Met573Thr	missense_variant	Exon 13 of 21		NP_246273.2
PDE5A	XM_017008791.3	c.1874T>C	p.Met625Thr	missense_variant	Exon 13 of 15		XP_016864280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE5A	ENST00000354960.8	c.1874T>C	p.Met625Thr	missense_variant	Exon 13 of 21	1	NM_001083.4	ENSP00000347046.3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 32 AN: 249518 Hom.: 1 AF XY: 0.000119 AC XY: 16 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000592

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1460132 Hom.: 3 Cov.: 30 AF XY: 0.0000867 AC XY: 63 AN XY: 726368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000721

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000689 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1874T>C (p.M625T) alteration is located in exon 13 (coding exon 13) of the PDE5A gene. This alteration results from a T to C substitution at nucleotide position 1874, causing the methionine (M) at amino acid position 625 to be replaced by a threonine (T). 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	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.83		Loss of MoRF binding (P = 0.0861);.;.;
MVP		0.97
MPC		1.1
ClinPred		0.42	T
GERP RS		5.9
Varity_R		0.88
gMVP		0.87

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: rs199872206; hg19: chr4-120442121;