5-58969778-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001104631.2(PDE4D):c.*4886A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 152,240 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.071 (429 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: PDE4D NM_001104631.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE4D	NM_001104631.2	c.*4886A>C		3_prime_UTR_variant	15/15	ENST00000340635.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE4D	ENST00000340635.11	c.*4886A>C		3_prime_UTR_variant	15/15	1	NM_001104631.2
PDE4D	ENST00000507116.6	c.*4886A>C		3_prime_UTR_variant	15/15	1		P4

Frequencies

GnomAD3 genomes AF: 0.0708 AC: 10775 AN: 152122 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0615

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0729

Gnomad OTH AF: 0.0626

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0708 AC: 10782 AN: 152240 Hom.: 429 Cov.: 32 AF XY: 0.0696 AC XY: 5184 AN XY: 74440

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.0707

Gnomad4 ASJ AF: 0.0615

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0695

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0729

Gnomad4 OTH AF: 0.0619

Alfa AF: 0.0782 Hom.: 202

Bravo AF: 0.0750

Asia WGS AF: 0.0320 AC: 114 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acrodysostosis 2 with or without hormone resistance Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.0
Dann	Benign	0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17291089; hg19: chr5-58265605;