4-119505936-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001083.4(PDE5A):c.2190-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,533,452 control chromosomes in the GnomAD database, including 29 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (24 hom.)
• Consequence: PDE5A NM_001083.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008263
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-119505936-C-T is Benign according to our data. Variant chr4-119505936-C-T is described in ClinVar as [Benign]. Clinvar id is 777148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.2190-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000354960.8
PDE5A	NM_033430.3	c.2064-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDE5A	NM_033437.4	c.2034-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8	c.2190-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001083.4
	ENST00000688315.1	n.1004-6415C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 709 AN: 151582 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00662

Gnomad OTH AF: 0.00674

GnomAD3 exomes AF: 0.00467 AC: 980 AN: 209884 Hom.: 4 AF XY: 0.00511 AC XY: 587 AN XY: 114940

Gnomad AFR exome AF: 0.000771

Gnomad AMR exome AF: 0.00577

Gnomad ASJ exome AF: 0.00579

Gnomad EAS exome AF: 0.0000677

Gnomad SAS exome AF: 0.00355

Gnomad FIN exome AF: 0.000239

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00609 AC: 8410 AN: 1381752 Hom.: 24 Cov.: 23 AF XY: 0.00600 AC XY: 4133 AN XY: 689232

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00487

Gnomad4 EAS exome AF: 0.0000538

Gnomad4 SAS exome AF: 0.00343

Gnomad4 FIN exome AF: 0.000548

Gnomad4 NFE exome AF: 0.00686

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00467 AC: 709 AN: 151700 Hom.: 5 Cov.: 32 AF XY: 0.00444 AC XY: 329 AN XY: 74118

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00764

Gnomad4 ASJ AF: 0.00578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.00667

Alfa AF: 0.00546 Hom.: 4

Bravo AF: 0.00511

Asia WGS AF: 0.00145 AC: 5 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.8
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.0020
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: rs142272118; hg19: chr4-120427091; COSMIC: COSV105868094; COSMIC: COSV105868094;