4-119542593-T-G

Position:

• chr4-119542593-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083.4(PDE5A):​c.1438A>C​(p.Lys480Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,950 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (15 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00514555).
• BP6: Variant 4-119542593-T-G is Benign according to our data. Variant chr4-119542593-T-G is described in ClinVar as [Benign]. Clinvar id is 724466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0077 (1173/152240) while in subpopulation AFR AF= 0.0266 (1104/41538). AF 95% confidence interval is 0.0253. There are 14 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE5A	NM_001083.4	c.1438A>C	p.Lys480Gln	missense_variant	10/21	ENST00000354960.8	NP_001074.2
PDE5A	NM_033430.3	c.1312A>C	p.Lys438Gln	missense_variant	10/21		NP_236914.2
PDE5A	NM_033437.4	c.1282A>C	p.Lys428Gln	missense_variant	10/21		NP_246273.2
PDE5A	XM_017008791.3	c.1438A>C	p.Lys480Gln	missense_variant	10/15		XP_016864280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE5A	ENST00000354960.8	c.1438A>C	p.Lys480Gln	missense_variant	10/21	1	NM_001083.4	ENSP00000347046
	ENST00000688315.1	n.1326-7786T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00770 AC: 1172 AN: 152122 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00207 AC: 520 AN: 251350 Hom.: 7 AF XY: 0.00155 AC XY: 210 AN XY: 135834

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000807 AC: 1180 AN: 1461710 Hom.: 15 Cov.: 31 AF XY: 0.000763 AC XY: 555 AN XY: 727160

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00770 AC: 1173 AN: 152240 Hom.: 14 Cov.: 32 AF XY: 0.00782 AC XY: 582 AN XY: 74446

Gnomad4 AFR AF: 0.0266

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00172 Hom.: 3

Bravo AF: 0.00856

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.075	B;.;P
Vest4		0.22
MVP		0.69
MPC		0.35
ClinPred		0.0094	T
GERP RS		1.4
Varity_R		0.20
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs114790192; hg19: chr4-120463748; COSMIC: COSV99049010; COSMIC: COSV99049010;