rs759832724

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000340635.11(PDE4D):​c.2179C>T​(p.Arg727Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R727Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PDE4D
ENST00000340635.11 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.800
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24313936).
BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDE4DNM_001104631.2 linkuse as main transcriptc.2179C>T p.Arg727Trp missense_variant 15/15 ENST00000340635.11 NP_001098101.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDE4DENST00000340635.11 linkuse as main transcriptc.2179C>T p.Arg727Trp missense_variant 15/151 NM_001104631.2 ENSP00000345502 Q08499-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248642
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1460610
Hom.:
0
Cov.:
33
AF XY:
0.00000826
AC XY:
6
AN XY:
726434
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 13, 2021The c.2179C>T (p.R727W) alteration is located in exon 15 (coding exon 15) of the PDE4D gene. This alteration results from a C to T substitution at nucleotide position 2179, causing the arginine (R) at amino acid position 727 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Acrodysostosis 2 with or without hormone resistance Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;T;T;.;.;.;.;.;.;.
Eigen
Benign
0.059
Eigen_PC
Benign
0.054
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.24
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
1.9
L;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
0.93
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.2
N;.;.;N;N;N;N;N;N;N
REVEL
Benign
0.19
Sift
Uncertain
0.014
D;.;.;D;D;D;D;D;D;D
Sift4G
Uncertain
0.016
D;D;.;D;D;D;D;D;D;D
Polyphen
0.98
D;.;.;.;D;.;P;P;D;D
Vest4
0.20
MutPred
0.33
Loss of solvent accessibility (P = 0.0036);.;.;.;.;.;.;.;.;.;
MVP
0.51
MPC
1.5
ClinPred
0.57
D
GERP RS
0.95
Varity_R
0.077
gMVP
0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759832724; hg19: chr5-58270742; API