NM_001083.4:c.2488G>C

Variant names:

• chr4-119501172-C-G
• rs199573045
• NM_001083.4:c.2488G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001083.4(PDE5A):​c.2488G>C​(p.Glu830Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000546 in 1,593,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense, splice_region
• Scores: Splicing: ADA: 0.2258
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61
• Publications: 1 publications found

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]

ENSG00000291203 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35141933).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE5A	NM_001083.4	MANE Select	c.2488G>C	p.Glu830Gln	missense splice_region	Exon 20 of 21	NP_001074.2	O76074-1
	PDE5A	NM_033430.3		c.2362G>C	p.Glu788Gln	missense splice_region	Exon 20 of 21	NP_236914.2	O76074-2
	PDE5A	NM_033437.4		c.2332G>C	p.Glu778Gln	missense splice_region	Exon 20 of 21	NP_246273.2	G5E9C5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE5A	ENST00000354960.8	TSL:1 MANE Select	c.2488G>C	p.Glu830Gln	missense splice_region	Exon 20 of 21	ENSP00000347046.3	O76074-1
	PDE5A	ENST00000264805.9	TSL:1	c.2362G>C	p.Glu788Gln	missense splice_region	Exon 20 of 21	ENSP00000264805.5	O76074-2
	PDE5A	ENST00000503412.1	TSL:3	c.541G>C	p.Glu181Gln	missense	Exon 7 of 7	ENSP00000425810.1	H0YA14

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000559 AC: 14 AN: 250630 AF XY: 0.0000369

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000326 AC: 47 AN: 1440840 Hom.: 0 Cov.: 26 AF XY: 0.0000265 AC XY: 19 AN XY: 718318

African (AFR) AF: 0.00121 AC: 40 AN: 33014

American (AMR) AF: 0.0000671 AC: 3 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093152

Other (OTH) AF: 0.0000503 AC: 3 AN: 59684

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74430

African (AFR) AF: 0.000915 AC: 38 AN: 41548

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.39
Sift	Benign	0.41	T
Sift4G	Benign	0.25	T
Polyphen		0.024	B
Vest4		0.61
MVP		0.93
MPC		0.37
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.47
gMVP		0.46
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.23
dbscSNV1_RF	Benign	0.41
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

Other links and lift over

dbSNP: rs199573045; hg19: chr4-120422327;