Genetic Variant NM_001111307.2:c.2207C>A (chr19-10467167-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3433 hom., cov: 31)

Exomes 𝑓: 0.18 ( 24426 hom. )

Consequence

PDE4A
NM_001111307.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.49

Publications

61 publications found

Variant links:

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]

PDE4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PDE4A	NM_001111307.2 link	c.2207C>A	p.Ala736Glu	missense_variant	Exon 15 of 15	ENST00000380702.7	NP_001104777.1	P27815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4A	ENST00000380702.7 link	c.2207C>A	p.Ala736Glu	missense_variant	Exon 15 of 15	1	NM_001111307.2	ENSP00000370078.3		P27815-1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30746

AN:

152026

Hom.:

3426

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.169

AC:

42579

AN:

251318

AF XY:

0.168

show subpopulations

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 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.:

AF XY:

0.178

AC XY:

129351

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.295

AC:

9870

AN:

33480

American (AMR)

AF:

0.115

AC:

5121

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

4749

AN:

26136

East Asian (EAS)

AF:

0.0984

AC:

3906

AN:

39698

South Asian (SAS)

AF:

0.156

AC:

13487

AN:

86256

European-Finnish (FIN)

AF:

0.130

AC:

6933

AN:

53408

Middle Eastern (MID)

AF:

0.204

AC:

1176

AN:

5768

European-Non Finnish (NFE)

AF:

0.185

AC:

205550

AN:

1111944

Other (OTH)

AF:

0.182

AC:

10983

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

13468

26937

40405

53874

67342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.202

AC:

30774

AN:

152144

Hom.:

3433

Cov.:

AF XY:

0.198

AC XY:

14761

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.288

AC:

11953

AN:

41500

American (AMR)

AF:

0.143

AC:

2186

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

704

AN:

3470

East Asian (EAS)

AF:

0.138

AC:

716

AN:

5180

South Asian (SAS)

AF:

0.154

AC:

741

AN:

4820

European-Finnish (FIN)

AF:

0.123

AC:

1300

AN:

10594

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.183

AC:

12419

AN:

67990

Other (OTH)

AF:

0.200

AC:

423

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1252

2503

3755

5006

6258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.185

Hom.:

9370

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.1

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.027

.;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.76

T;T;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.;.;.

PhyloP100

-1.5

PrimateAI

Benign

0.27

PROVEAN

Benign

0.070

.;.;N;N;N

REVEL

Benign

0.043

Sift

Uncertain

0.021

.;.;D;D;D

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

GERP RS

-4.4

Varity_R

0.073

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_001111307.2:c.2207C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over