Variant 4-119504547-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001083.4(PDE5A):c.2320A>G(p.Ile774Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PDE5A
NM_001083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15980834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDE5A	NM_001083.4 linkuse as main transcript	c.2320A>G	p.Ile774Val	missense_variant	18/21	ENST00000354960.8
PDE5A	NM_033430.3 linkuse as main transcript	c.2194A>G	p.Ile732Val	missense_variant	18/21
PDE5A	NM_033437.4 linkuse as main transcript	c.2164A>G	p.Ile722Val	missense_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8 linkuse as main transcript	c.2320A>G	p.Ile774Val	missense_variant	18/21	1	NM_001083.4		O76074-1
	ENST00000688315.1 linkuse as main transcript	n.1003+6644T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248710

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134506

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1459456

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.000479

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000655

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.2320A>G (p.I774V) alteration is located in exon 18 (coding exon 18) of the PDE5A gene. This alteration results from a A to G substitution at nucleotide position 2320, causing the isoleucine (I) at amino acid position 774 to be replaced by a valine (V). 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

0.050

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.16

T;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.065

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

0.33

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.97

T;T;T

Sift4G

Benign

0.91

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.21

MVP

0.83

MPC

0.27

ClinPred

0.034

GERP RS

4.3

Varity_R

0.13

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over