rs397514466

Positions:

• chr5-59215856-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_001104631.2(PDE4D):​c.568T>G​(p.Ser190Ala) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S190F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE4D NM_001104631.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.31

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-59215855-G-A is described in Lovd as [Pathogenic].
• PP5: Variant 5-59215856-A-C is Pathogenic according to our data. Variant chr5-59215856-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 30037.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-59215856-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.568T>G	p.Ser190Ala	missense_variant	2/15	ENST00000340635.11	NP_001098101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11	c.568T>G	p.Ser190Ala	missense_variant	2/15	1	NM_001104631.2	ENSP00000345502.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acrodysostosis 2 with or without hormone resistance Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 06, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;T;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N;.;.;N;N;N;N;N;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;.;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;.;D;D;D;D;D;D;.
Polyphen		0.0040	B;.;.;.;P;B;D;P;D;.
Vest4		0.84
MutPred		0.24		Loss of phosphorylation at S190 (P = 0.0108);.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		1.7
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.25
gMVP		0.89

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

Other links and lift over

dbSNP: rs397514466; hg19: chr5-58511682;