4-119542606-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001083.4(PDE5A):c.1425G>A(p.Glu475=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,613,854 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: PDE5A NM_001083.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.196

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 4-119542606-C-T is Benign according to our data. Variant chr4-119542606-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 779420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.196 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.1425G>A	p.Glu475=	synonymous_variant	10/21	ENST00000354960.8
PDE5A	NM_033430.3	c.1299G>A	p.Glu433=	synonymous_variant	10/21
PDE5A	NM_033437.4	c.1269G>A	p.Glu423=	synonymous_variant	10/21
PDE5A	XM_017008791.3	c.1425G>A	p.Glu475=	synonymous_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8	c.1425G>A	p.Glu475=	synonymous_variant	10/21	1	NM_001083.4
	ENST00000688315.1	n.1326-7773C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152108 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00222 AC: 557 AN: 251254 Hom.: 2 AF XY: 0.00225 AC XY: 306 AN XY: 135790

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00369 AC: 5387 AN: 1461628 Hom.: 19 Cov.: 31 AF XY: 0.00361 AC XY: 2622 AN XY: 727112

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152226 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74436

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00298 Hom.: 1

Bravo AF: 0.00221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PDE5A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	6.6
Dann	Benign	0.88

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: rs148360694; hg19: chr4-120463761;