rs397515433

Variant names:

• chr5-59038869-G-A
• rs397515433
• NM_001104631.2:c.911C>T
• PDE4D p.Ala304Val

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.93
• Publications: 7 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

PDE4D-AS1 (HGNC:58182):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001104631.2
• 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 VariationId is 40064.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	NM_001104631.2	MANE Select	c.911C>T	p.Ala304Val	missense	Exon 6 of 15	NP_001098101.1	A0A140VJR0
	PDE4D	NM_001165899.2		c.728C>T	p.Ala243Val	missense	Exon 8 of 17	NP_001159371.1	Q08499-11
	PDE4D	NM_001364599.1		c.728C>T	p.Ala243Val	missense	Exon 8 of 17	NP_001351528.1	Q08499-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.911C>T	p.Ala304Val	missense	Exon 6 of 15	ENSP00000345502.6	Q08499-1
	PDE4D	ENST00000502484.6	TSL:1	c.728C>T	p.Ala243Val	missense	Exon 8 of 17	ENSP00000423094.2	Q08499-11
	PDE4D	ENST00000507116.6	TSL:1	c.719C>T	p.Ala240Val	missense	Exon 6 of 15	ENSP00000424852.1	Q08499-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.08e-7 AC: 1 AN: 1412062 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698642

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

African (AFR) AF: 0.00 AC: 0 AN: 31530

American (AMR) AF: 0.00 AC: 0 AN: 38422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23638

East Asian (EAS) AF: 0.00 AC: 0 AN: 37004

South Asian (SAS) AF: 0.00 AC: 0 AN: 78894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086922

Other (OTH) AF: 0.00 AC: 0 AN: 58192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acrodysostosis 2 with or without hormone resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.028	D
Sift4G	Benign	0.097	T
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)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397515433;

hg19: chr5-58334696;