Genetic Variant PDE4A:p.Thr304Arg (chr19-10457912-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001111307.2(PDE4A):c.911C>G(p.Thr304Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T304M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PDE4A
NM_001111307.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.896

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16979599).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111307.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4A	NM_001111307.2	MANE Select	c.911C>G	p.Thr304Arg	missense	Exon 8 of 15	NP_001104777.1	P27815-1
PDE4A	NM_001243121.2		c.845C>G	p.Thr282Arg	missense	Exon 10 of 17	NP_001230050.1	P27815-7
PDE4A	NM_001111308.1		c.833C>G	p.Thr278Arg	missense	Exon 8 of 15	NP_001104778.1	P27815-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4A	ENST00000380702.7	TSL:1 MANE Select	c.911C>G	p.Thr304Arg	missense	Exon 8 of 15	ENSP00000370078.3	P27815-1
PDE4A	ENST00000592685.5	TSL:1	c.845C>G	p.Thr282Arg	missense	Exon 10 of 17	ENSP00000468507.1	P27815-7
PDE4A	ENST00000293683.9	TSL:1	c.833C>G	p.Thr278Arg	missense	Exon 8 of 15	ENSP00000293683.4	P27815-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460356

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4544

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.059

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.3

PhyloP100

0.90

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.21

Sift

Benign

0.12

Sift4G

Benign

0.19

Polyphen

0.97

Vest4

0.54

MutPred

0.24

Loss of glycosylation at T304 (P = 0.0099)

MVP

0.57

ClinPred

0.98

GERP RS

1.8

Varity_R

0.36

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over