Variant 4-119502654-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001083.4(PDE5A):c.2333T>C(p.Ile778Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,591,628 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 14 hom. )

Consequence

PDE5A
NM_001083.4 missense, splice_region

Scores

Splicing: ADA: 0.7615

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.32

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17800876).

BP6

Variant 4-119502654-A-G is Benign according to our data. Variant chr4-119502654-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 779419.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PDE5A	NM_001083.4 linkuse as main transcript	c.2333T>C	p.Ile778Thr	missense_variant, splice_region_variant	19/21	ENST00000354960.8
PDE5A	NM_033430.3 linkuse as main transcript	c.2207T>C	p.Ile736Thr	missense_variant, splice_region_variant	19/21
PDE5A	NM_033437.4 linkuse as main transcript	c.2177T>C	p.Ile726Thr	missense_variant, splice_region_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8 linkuse as main transcript	c.2333T>C	p.Ile778Thr	missense_variant, splice_region_variant	19/21	1	NM_001083.4		O76074-1
	ENST00000688315.1 linkuse as main transcript	n.1003+4751A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

223

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00133

AC:

328

AN:

247158

Hom.:

AF XY:

0.00142

AC XY:

189

AN XY:

133502

show subpopulations

Gnomad AFR exome

AF:

0.000618

Gnomad AMR exome

AF:

0.000708

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000710

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00293

AC:

4224

AN:

1439356

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2053

AN XY:

716966

show subpopulations

Gnomad4 AFR exome

AF:

0.000638

Gnomad4 AMR exome

AF:

0.000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.000227

Gnomad4 NFE exome

AF:

0.00355

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152272

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00269

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00146

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00361

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00273

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;D;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.87

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Pathogenic

0.72

Sift

Benign

0.034

D;D;D

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.87

P;.;P

Vest4

0.93

MVP

0.93

MPC

1.2

ClinPred

0.087

GERP RS

6.1

Varity_R

0.69

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.76

dbscSNV1_RF

Benign

0.56

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