rs397514466

Variant names:

• chr5-59215856-A-C
• rs397514466
• NM_001104631.2:c.568T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. S190Y) has been classified as Uncertain significance.

• 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
• Publications: 11 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 ClinVar as [Likely_pathogenic]. Clinvar id is 982782.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.568T>G	p.Ser190Ala	missense_variant	Exon 2 of 15	ENST00000340635.11	NP_001098101.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acrodysostosis 2 with or without hormone resistance Pathogenic:1

Apr 06, 2012

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	0.91
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;.;.;.;.;.;.;.;.;.
PhyloP100		7.3
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514466; hg19: chr5-58511682;