19-10463800-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001111307.2(PDE4A):c.1751G>A(p.Arg584Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PDE4A NM_001111307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

PDE4A (HGNC:8780): (phosphodiesterase 4A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030717075).
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE4A	NM_001111307.2	c.1751G>A	p.Arg584Gln	missense_variant	14/15	ENST00000380702.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE4A	ENST00000380702.7	c.1751G>A	p.Arg584Gln	missense_variant	14/15	1	NM_001111307.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251238 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 138 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152110 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.1751G>A (p.R584Q) alteration is located in exon 14 (coding exon 14) of the PDE4A gene. This alteration results from a G to A substitution at nucleotide position 1751, causing the arginine (R) at amino acid position 584 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Benign	0.38
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.50, 0.28, 0.99, 1.0	.;P;B;D;D
Vest4		0.17
MVP		0.80
ClinPred		0.035	T
GERP RS		3.3
Varity_R		0.065

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: rs200669683; hg19: chr19-10574476; COSMIC: COSV53350203; COSMIC: COSV53350203;