rs829259

Positions:

• chr5-58972149-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001104631.2(PDE4D):​c.*2515A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 152,374 control chromosomes in the GnomAD database, including 26,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26217 hom., cov: 31)
  • Exomes 𝑓: 0.60 (84 hom.)
• Consequence: PDE4D NM_001104631.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.382

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-58972149-T-A is Benign according to our data. Variant chr5-58972149-T-A is described in ClinVar as [Benign]. Clinvar id is 353941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.*2515A>T		3_prime_UTR_variant	15/15	ENST00000340635.11	NP_001098101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11	c.*2515A>T		3_prime_UTR_variant	15/15	1	NM_001104631.2	ENSP00000345502
PDE4D	ENST00000507116.6	c.*2515A>T		3_prime_UTR_variant	15/15	1		ENSP00000424852	P4
PDE4D	ENST00000636120.1	c.*2515A>T		3_prime_UTR_variant	15/15	5		ENSP00000490821

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88938 AN: 151828 Hom.: 26203 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.617

GnomAD4 exome AF: 0.598 AC: 256 AN: 428 Hom.: 84 Cov.: 0 AF XY: 0.569 AC XY: 148 AN XY: 260

Gnomad4 FIN exome AF: 0.595

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.586 AC: 88989 AN: 151946 Hom.: 26217 Cov.: 31 AF XY: 0.584 AC XY: 43376 AN XY: 74252

Gnomad4 AFR AF: 0.513

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.663

Gnomad4 EAS AF: 0.659

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.616

Alfa AF: 0.597 Hom.: 3408

Bravo AF: 0.590

Asia WGS AF: 0.638 AC: 2219 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Acrodysostosis 2 with or without hormone resistance Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.26
DANN	Benign	0.69

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs829259; hg19: chr5-58267976;