rs1051738

chr19-10467167-C-Achr19-10467167-C-Gchr19-10467167-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001111307.2(PDE4A):c.2207C>A(p.Ala736Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,952 control chromosomes in the GnomAD database, including 27,859 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3433 hom., cov: 31)
  • Exomes 𝑓: 0.18 (24426 hom.)
• Consequence: PDE4A NM_001111307.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049764514).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE4A	NM_001111307.2	c.2207C>A	p.Ala736Glu	missense_variant	15/15	ENST00000380702.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE4A	ENST00000380702.7	c.2207C>A	p.Ala736Glu	missense_variant	15/15	1	NM_001111307.2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30746 AN: 152026 Hom.: 3426 Cov.: 31

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.169 AC: 42579 AN: 251318 Hom.: 3850 AF XY: 0.168 AC XY: 22872 AN XY: 135850

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.179 AC: 261775 AN: 1461808 Hom.: 24426 Cov.: 34 AF XY: 0.178 AC XY: 129351 AN XY: 727208

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.0984

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.202 AC: 30774 AN: 152144 Hom.: 3433 Cov.: 31 AF XY: 0.198 AC XY: 14761 AN XY: 74384

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.200

Alfa AF: 0.179 Hom.: 5790

Bravo AF: 0.209

TwinsUK AF: 0.183 AC: 678

ALSPAC AF: 0.188 AC: 723

ESP6500AA AF: 0.286 AC: 1259

ESP6500EA AF: 0.179 AC: 1536

ExAC AF: 0.176 AC: 21416

Asia WGS AF: 0.127 AC: 440 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	1.1
Dann	Benign	0.88
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.76	T;T;T;T;T
MetaRNN	Benign	0.0050	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.22, 0.85, 0.71, 0.52	.;B;P;P;P
Vest4		0.040
ClinPred		0.0075	T
GERP RS		-4.4
Varity_R		0.073

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: rs1051738; hg19: chr19-10577843; COSMIC: COSV53352220;