Genetic Variant PDE4D:c.455+123204A>G (chr5-59769964-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001104631.2(PDE4D):c.455+123204A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,944 control chromosomes in the GnomAD database, including 19,334 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19334 hom., cov: 31)

Consequence

PDE4D
NM_001104631.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

4 publications found

Variant links:

Genes affected

PDE4D (HGNC:8783): (phosphodiesterase 4D) This gene encodes one of four mammalian counterparts to the fruit fly 'dunce' gene. The encoded protein has 3',5'-cyclic-AMP phosphodiesterase activity and degrades cAMP, which acts as a signal transduction molecule in multiple cell types. This gene uses different promoters to generate multiple alternatively spliced transcript variants that encode functional proteins.[provided by RefSeq, Sep 2009]

PDE4D Gene-Disease associations (from GenCC):

acrodysostosis 2 with or without hormone resistance
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
acrodysostosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acrodysostosis with multiple hormone resistance
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
chromosome 5q12 deletion syndrome
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

PDE4D links:

ENSG00000309959 (HGNC:):

ENSG00000309959 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001104631.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE4D	NM_001104631.2	MANE Select	c.455+123204A>G	intron	N/A	NP_001098101.1	A0A140VJR0
PDE4D	NM_001165899.2		c.272+218524A>G	intron	N/A	NP_001159371.1	Q08499-11
PDE4D	NM_001364599.1		c.272+218524A>G	intron	N/A	NP_001351528.1	Q08499-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.455+123204A>G	intron	N/A	ENSP00000345502.6	Q08499-1
PDE4D	ENST00000502484.6	TSL:1	c.272+218524A>G	intron	N/A	ENSP00000423094.2	Q08499-11
PDE4D	ENST00000405053.7	TSL:5	n.118+123204A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74451

AN:

151826

Hom.:

19309

Cov.:

show subpopulations

Gnomad AFR

AF:

0.632

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.408

Gnomad ASJ

AF:

0.433

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.512

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.490

AC:

74517

AN:

151944

Hom.:

19334

Cov.:

AF XY:

0.487

AC XY:

36178

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.632

AC:

26169

AN:

41394

American (AMR)

AF:

0.408

AC:

6226

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.433

AC:

1499

AN:

3464

East Asian (EAS)

AF:

0.142

AC:

735

AN:

5184

South Asian (SAS)

AF:

0.393

AC:

1893

AN:

4818

European-Finnish (FIN)

AF:

0.512

AC:

5400

AN:

10554

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.457

AC:

31030

AN:

67946

Other (OTH)

AF:

0.458

AC:

966

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1791

3581

5372

7162

8953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

644

1288

1932

2576

3220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.440

Hom.:

4444

Bravo

AF:

0.487

Asia WGS

AF:

0.302

AC:

1051

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.4

(source)

DANN

Benign

0.51

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over