4-119504547-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083.4(PDE5A):​c.2320A>C​(p.Ile774Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,456 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I774V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Ile774Leu	missense	Exon 18 of 21	NP_001074.2	O76074-1
	PDE5A	NM_033430.3		c.2194A>C	p.Ile732Leu	missense	Exon 18 of 21	NP_236914.2	O76074-2
	PDE5A	NM_033437.4		c.2164A>C	p.Ile722Leu	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>C	p.Ile774Leu	missense	Exon 18 of 21	ENSP00000347046.3	O76074-1
	PDE5A	ENST00000264805.9	TSL:1	c.2194A>C	p.Ile732Leu	missense	Exon 18 of 21	ENSP00000264805.5	O76074-2
	PDE5A	ENST00000925607.1		c.2317A>C	p.Ile773Leu	missense	Exon 18 of 21	ENSP00000595666.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459456 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726080

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110486

Other (OTH) AF: 0.0000166 AC: 1 AN: 60248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.037	B
Vest4		0.52
MutPred		0.72		Loss of methylation at K770 (P = 0.1008)
MVP		0.84
MPC		0.34
ClinPred		0.77	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.51
Mutation Taster		=82/18	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;