Genetic Variant NM_001111307.2:c.1339G>C (chr19-10459733-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001111307.2(PDE4A):c.1339G>C(p.Val447Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V447I) 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: 6.68

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.1339G>C	p.Val447Leu	missense	Exon 10 of 15	NP_001104777.1	P27815-1
PDE4A	NM_001243121.2		c.1273G>C	p.Val425Leu	missense	Exon 12 of 17	NP_001230050.1	P27815-7
PDE4A	NM_001111308.1		c.1261G>C	p.Val421Leu	missense	Exon 10 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.1339G>C	p.Val447Leu	missense	Exon 10 of 15	ENSP00000370078.3	P27815-1
PDE4A	ENST00000592685.5	TSL:1	c.1273G>C	p.Val425Leu	missense	Exon 12 of 17	ENSP00000468507.1	P27815-7
PDE4A	ENST00000293683.9	TSL:1	c.1261G>C	p.Val421Leu	missense	Exon 10 of 15	ENSP00000293683.4	P27815-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111444

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.96

PhyloP100

6.7

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.38

Sift

Uncertain

0.013

Sift4G

Uncertain

0.030

Polyphen

0.77

Vest4

0.80

MutPred

0.48

Loss of glycosylation at S444 (P = 0.1046)

MVP

0.63

ClinPred

0.97

GERP RS

4.8

Varity_R

0.86

Mutation Taster

=54/46

polymorphism

(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

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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