4-119502654-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

8 publications found

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:

ENSG00000291203 (HGNC:):

ENSG00000291203 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 779419.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE5A	NM_001083.4	MANE Select	c.2333T>C	p.Ile778Thr	missense splice_region	Exon 19 of 21	NP_001074.2	O76074-1
PDE5A	NM_033430.3		c.2207T>C	p.Ile736Thr	missense splice_region	Exon 19 of 21	NP_236914.2	O76074-2
PDE5A	NM_033437.4		c.2177T>C	p.Ile726Thr	missense splice_region	Exon 19 of 21	NP_246273.2	G5E9C5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE5A	ENST00000354960.8	TSL:1 MANE Select	c.2333T>C	p.Ile778Thr	missense splice_region	Exon 19 of 21	ENSP00000347046.3	O76074-1
PDE5A	ENST00000264805.9	TSL:1	c.2207T>C	p.Ile736Thr	missense splice_region	Exon 19 of 21	ENSP00000264805.5	O76074-2
PDE5A	ENST00000925607.1		c.2330T>C	p.Ile777Thr	missense splice_region	Exon 19 of 21	ENSP00000595666.1

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

GnomAD2 exomes

AF:

0.00133

AC:

328

AN:

247158

AF XY:

0.00142

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 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

African (AFR)

AF:

0.000638

AC:

AN:

32900

American (AMR)

AF:

0.000840

AC:

AN:

44068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39472

South Asian (SAS)

AF:

0.000800

AC:

AN:

85032

European-Finnish (FIN)

AF:

0.000227

AC:

AN:

52946

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00355

AC:

3888

AN:

1093786

Other (OTH)

AF:

0.00331

AC:

197

AN:

59542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

171

342

514

685

856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152272

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41570

American (AMR)

AF:

0.00105

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00269

AC:

183

AN:

68010

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00206

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.052

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.87

PhyloP100

8.3

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.72

Sift

Benign

0.034

Sift4G

Uncertain

0.037

Polyphen

0.87

Vest4

0.93

MVP

0.93

MPC

1.2

ClinPred

0.087

GERP RS

6.1

Varity_R

0.69

gMVP

0.60

Mutation Taster

=62/38

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over