5-59193502-G-C

Variant names:

• chr5-59193502-G-C
• rs397514468
• NM_001104631.2:c.682C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001104631.2(PDE4D):​c.682C>G​(p.Gln228Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE4D NM_001104631.2 missense, splice_region
• Scores: Splicing: ADA: 0.9267
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.68
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001104631.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 5-59193502-G-C is Pathogenic according to our data. Variant chr5-59193502-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30039.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	NM_001104631.2	MANE Select	c.682C>G	p.Gln228Glu	missense splice_region	Exon 3 of 15	NP_001098101.1
	PDE4D	NM_001349243.2		c.-13C>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 17	NP_001336172.1
	PDE4D	NM_001364604.1		c.-13C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001351533.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.682C>G	p.Gln228Glu	missense splice_region	Exon 3 of 15	ENSP00000345502.6
	PDE4D	ENST00000502484.6	TSL:1	c.499C>G	p.Gln167Glu	missense splice_region	Exon 5 of 17	ENSP00000423094.2
	PDE4D	ENST00000507116.6	TSL:1	c.490C>G	p.Gln164Glu	missense splice_region	Exon 3 of 15	ENSP00000424852.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDE4D function (PMID: 24203977). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30039). This missense change has been observed in individual(s) with acrodysostosis (PMID: 22464252). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 228 of the PDE4D protein (p.Gln228Glu).

Acrodysostosis 2 with or without hormone resistance Pathogenic:1

Feb 28, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.042	D
Polyphen		0.71	P
Vest4		0.83
MutPred		0.47		Loss of MoRF binding (P = 0.0936)
MVP		0.98
MPC		1.9
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.52
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.62
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: rs397514468; hg19: chr5-58489328;