4-119504547-T-C

Variant names:

• chr4-119504547-T-C
• rs200968351
• NM_001083.4:c.2320A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001083.4(PDE5A):​c.2320A>G​(p.Ile774Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15980834).

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.2320A>G	p.Ile774Val	missense	Exon 18 of 21	NP_001074.2	O76074-1
	PDE5A	NM_033430.3		c.2194A>G	p.Ile732Val	missense	Exon 18 of 21	NP_236914.2	O76074-2
	PDE5A	NM_033437.4		c.2164A>G	p.Ile722Val	missense	Exon 18 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.2320A>G	p.Ile774Val	missense	Exon 18 of 21	ENSP00000347046.3	O76074-1
	PDE5A	ENST00000264805.9	TSL:1	c.2194A>G	p.Ile732Val	missense	Exon 18 of 21	ENSP00000264805.5	O76074-2
	PDE5A	ENST00000925607.1		c.2317A>G	p.Ile773Val	missense	Exon 18 of 21	ENSP00000595666.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248710 AF XY: 0.0000446

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1459456 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 18 AN XY: 726080

African (AFR) AF: 0.000479 AC: 16 AN: 33374

American (AMR) AF: 0.0000224 AC: 1 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86048

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1110486

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74280

African (AFR) AF: 0.000145 AC: 6 AN: 41430

American (AMR) AF: 0.000131 AC: 2 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000886 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000412 AC: 5

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	0.050
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.065	N
PhyloP100		2.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.20
Sift	Benign	0.97	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.83
MPC		0.27
ClinPred		0.034	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.15
Mutation Taster		=87/13	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: rs200968351; hg19: chr4-120425702;