Genetic Variant PDE4D:p.Ala304Val (chr5-59038869-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_001104631.2(PDE4D):c.911C>T(p.Ala304Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PDE4D
NM_001104631.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.93

Publications

7 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:

ENSG00000247345 (HGNC:58182):

ENSG00000247345 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-59038869-G-A is Pathogenic according to our data. Variant chr5-59038869-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 40064.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4D	NM_001104631.2 link	c.911C>T	p.Ala304Val	missense_variant	Exon 6 of 15	ENST00000340635.11	NP_001098101.1	Q08499-1A0A140VJR0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11 link	c.911C>T	p.Ala304Val	missense_variant	Exon 6 of 15	1	NM_001104631.2	ENSP00000345502.6		Q08499-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.08e-7

AC:

AN:

1412062

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698642

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31530

American (AMR)

AF:

0.00

AC:

AN:

38422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23638

East Asian (EAS)

AF:

0.00

AC:

AN:

37004

South Asian (SAS)

AF:

0.00

AC:

AN:

78894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086922

Other (OTH)

AF:

0.00

AC:

AN:

58192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Acrodysostosis 2 with or without hormone resistance

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;T;T;.;.;.;.;.;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.64

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.3

D;.;.;D;D;D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.028

D;.;.;D;D;D;D;D;D;D

Sift4G

Benign

0.097

T;T;.;T;T;D;T;T;T;.

Polyphen

0.15

B;.;.;.;B;.;B;B;B;.

Vest4

0.66

MutPred

0.22

Gain of methylation at K307 (P = 0.0916);.;.;.;.;.;.;.;.;.;

MVP

0.92

MPC

1.8

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.85

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over