chr4-119521050-C-T

Variant names:

• chr4-119521050-C-T
• rs1726111452
• NM_001083.4:c.1790G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001083.4(PDE5A):​c.1790G>A​(p.Arg597Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35677785).

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.1790G>A	p.Arg597Lys	missense	Exon 13 of 21	NP_001074.2	O76074-1
	PDE5A	NM_033430.3		c.1664G>A	p.Arg555Lys	missense	Exon 13 of 21	NP_236914.2	O76074-2
	PDE5A	NM_033437.4		c.1634G>A	p.Arg545Lys	missense	Exon 13 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.1790G>A	p.Arg597Lys	missense	Exon 13 of 21	ENSP00000347046.3	O76074-1
	PDE5A	ENST00000264805.9	TSL:1	c.1664G>A	p.Arg555Lys	missense	Exon 13 of 21	ENSP00000264805.5	O76074-2
	ENSG00000291203	ENST00000500559.6	TSL:1	n.201-7690C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458580 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725482

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110490

Other (OTH) AF: 0.0000332 AC: 2 AN: 60248

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

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	0.12
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.094
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Benign	0.089	T
Sift4G	Uncertain	0.059	T
Polyphen		0.0040	B
Vest4		0.23
MutPred		0.62		Gain of methylation at R597 (P = 0.0017)
MVP		0.73
MPC		0.32
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.56
gMVP		0.60
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1726111452; hg19: chr4-120442205;