5-59546948-C-T

Variant names:

• chr5-59546948-C-T
• rs702543
• NM_001104631.2:c.456-330980G>A

Variant summary

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

The NM_001104631.2(PDE4D):​c.456-330980G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 151,948 control chromosomes in the GnomAD database, including 18,500 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 0.45 (18500 hom., cov: 32)
• Consequence: PDE4D NM_001104631.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• Publications: 16 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.456-330980G>A		intron_variant	Intron 1 of 14	ENST00000340635.11	NP_001098101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11	c.456-330980G>A		intron_variant	Intron 1 of 14	1	NM_001104631.2	ENSP00000345502.6

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68273 AN: 151830 Hom.: 18504 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.482

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

GnomAD4 genome AF: 0.449 AC: 68267 AN: 151948 Hom.: 18500 Cov.: 32 AF XY: 0.451 AC XY: 33499 AN XY: 74254

African (AFR) AF: 0.126 AC: 5226 AN: 41454

American (AMR) AF: 0.523 AC: 7971 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2292 AN: 3470

East Asian (EAS) AF: 0.625 AC: 3232 AN: 5170

South Asian (SAS) AF: 0.616 AC: 2973 AN: 4828

European-Finnish (FIN) AF: 0.533 AC: 5624 AN: 10546

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39308 AN: 67918

Other (OTH) AF: 0.488 AC: 1028 AN: 2108

Alfa AF: 0.545 Hom.: 102028

Bravo AF: 0.436

Asia WGS AF: 0.621 AC: 2155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.12
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: rs702543; hg19: chr5-58842774;