chr4-119505903-C-T

Position:

• chr4-119505903-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001083.4(PDE5A):​c.2219G>A​(p.Arg740Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 1,567,908 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (72 hom.)
• Consequence: PDE5A NM_001083.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.40

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053169727).
• BP6: Variant 4-119505903-C-T is Benign according to our data. Variant chr4-119505903-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 708681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-119505903-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE5A	NM_001083.4	c.2219G>A	p.Arg740Lys	missense_variant	17/21	ENST00000354960.8
PDE5A	NM_033430.3	c.2093G>A	p.Arg698Lys	missense_variant	17/21
PDE5A	NM_033437.4	c.2063G>A	p.Arg688Lys	missense_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE5A	ENST00000354960.8	c.2219G>A	p.Arg740Lys	missense_variant	17/21	1	NM_001083.4
	ENST00000688315.1	n.1004-6448C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 712 AN: 151580 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00316

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00275

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00578

GnomAD3 exomes AF: 0.00414 AC: 894 AN: 215798 Hom.: 2 AF XY: 0.00450 AC XY: 529 AN XY: 117600

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00312

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00494

GnomAD4 exome AF: 0.00777 AC: 11008 AN: 1416210 Hom.: 72 Cov.: 27 AF XY: 0.00776 AC XY: 5469 AN XY: 704586

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.00453

Gnomad4 NFE exome AF: 0.00915

Gnomad4 OTH exome AF: 0.00711

GnomAD4 genome AF: 0.00469 AC: 711 AN: 151698 Hom.: 4 Cov.: 32 AF XY: 0.00424 AC XY: 314 AN XY: 74120

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00316

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00275

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00572

Alfa AF: 0.00551 Hom.: 0

Bravo AF: 0.00447

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00583 AC: 50

ExAC AF: 0.00424 AC: 515

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.28	N;.;.
MutationTaster	Benign	0.85	D;D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.14
MVP		0.77
MPC		0.32
ClinPred		0.012	T
GERP RS		3.9
Varity_R		0.54
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139979143; hg19: chr4-120427058; COSMIC: COSV99048997; COSMIC: COSV99048997;