4-119519123-A-G

Variant names:

• chr4-119519123-A-G
• rs116396619
• NM_001083.4:c.1922T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001083.4(PDE5A):​c.1922T>C​(p.Leu641Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00073 in 1,613,568 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.10
• Publications: 6 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028883189).
• BP6: Variant 4-119519123-A-G is Benign according to our data. Variant chr4-119519123-A-G is described in ClinVar as Benign. ClinVar VariationId is 729052.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 gene

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.1922T>C	p.Leu641Pro	missense	Exon 14 of 21	NP_001074.2	O76074-1
	PDE5A	NM_033430.3		c.1796T>C	p.Leu599Pro	missense	Exon 14 of 21	NP_236914.2	O76074-2
	PDE5A	NM_033437.4		c.1766T>C	p.Leu589Pro	missense	Exon 14 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.1922T>C	p.Leu641Pro	missense	Exon 14 of 21	ENSP00000347046.3	O76074-1
	PDE5A	ENST00000264805.9	TSL:1	c.1796T>C	p.Leu599Pro	missense	Exon 14 of 21	ENSP00000264805.5	O76074-2
	ENSG00000291203	ENST00000500559.6	TSL:1	n.200+6203A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.000191

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00104 AC: 261 AN: 251084 AF XY: 0.000707

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000409 AC: 598 AN: 1461218 Hom.: 5 Cov.: 29 AF XY: 0.000365 AC XY: 265 AN XY: 726958

African (AFR) AF: 0.0123 AC: 411 AN: 33464

American (AMR) AF: 0.000604 AC: 27 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000684 AC: 76 AN: 1111458

Other (OTH) AF: 0.00113 AC: 68 AN: 60356

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74512

African (AFR) AF: 0.0127 AC: 528 AN: 41584

American (AMR) AF: 0.00209 AC: 32 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00151 Hom.: 2

Bravo AF: 0.00433

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.95
MVP		0.98
MPC		1.4
ClinPred		0.075	T
GERP RS		5.5
PromoterAI		0.048	Neutral
Varity_R		0.96
gMVP		0.96
Mutation Taster		=70/30	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: rs116396619; hg19: chr4-120440278;