4-119502654-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

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

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 Likely_benign. Variant got -4 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.2333T>C	p.Ile778Thr	missense_variant, splice_region_variant	19/21	ENST00000354960.8
PDE5A	NM_033430.3	c.2207T>C	p.Ile736Thr	missense_variant, splice_region_variant	19/21
PDE5A	NM_033437.4	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	c.2333T>C	p.Ile778Thr	missense_variant, splice_region_variant	19/21	1	NM_001083.4
	ENST00000688315.1	n.1003+4751A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152154 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00142 AC XY: 189 AN XY: 133502

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.: 14 Cov.: 26 AF XY: 0.00286 AC XY: 2053 AN XY: 716966

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.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74460

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.: 0

Bravo AF: 0.00146

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00273

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;D;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.87	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
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	T
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

Other links and lift over

dbSNP: rs114886951; hg19: chr4-120423809; COSMIC: COSV53351095; COSMIC: COSV53351095;