5-59606407-T-C

Variant names:

• chr5-59606407-T-C
• rs296410
• NM_001104631.2:c.455+286761A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001104631.2(PDE4D):​c.455+286761A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 151,994 control chromosomes in the GnomAD database, including 14,562 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (14562 hom., cov: 32)
• Consequence: PDE4D NM_001104631.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

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.455+286761A>G		intron	N/A	NP_001098101.1
	PDE4D	NM_001165899.2		c.272+382081A>G		intron	N/A	NP_001159371.1
	PDE4D	NM_001364599.1		c.272+382081A>G		intron	N/A	NP_001351528.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.455+286761A>G		intron	N/A	ENSP00000345502.6
	PDE4D	ENST00000502484.6	TSL:1	c.272+382081A>G		intron	N/A	ENSP00000423094.2
	PDE4D	ENST00000507116.6	TSL:1	c.263+161840A>G		intron	N/A	ENSP00000424852.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60046 AN: 151876 Hom.: 14562 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.425

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.395 AC: 60050 AN: 151994 Hom.: 14562 Cov.: 32 AF XY: 0.400 AC XY: 29723 AN XY: 74284

African (AFR) AF: 0.104 AC: 4322 AN: 41498

American (AMR) AF: 0.480 AC: 7327 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2058 AN: 3468

East Asian (EAS) AF: 0.727 AC: 3750 AN: 5160

South Asian (SAS) AF: 0.536 AC: 2579 AN: 4816

European-Finnish (FIN) AF: 0.499 AC: 5273 AN: 10564

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33189 AN: 67928

Other (OTH) AF: 0.433 AC: 913 AN: 2108

Alfa AF: 0.476 Hom.: 31792

Bravo AF: 0.383

Asia WGS AF: 0.622 AC: 2159 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.7
DANN	Benign	0.81
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs296410; hg19: chr5-58902233; COSMIC: COSV58963148;