rs702531

Positions:

• chr5-58971896-A-C
• chr5-58971896-A-T

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.*2768T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 152,336 control chromosomes in the GnomAD database, including 32,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (32871 hom., cov: 31)
  • Exomes 𝑓: 0.65 (98 hom.)
• Consequence: PDE4D NM_001104631.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.47

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=-0.58).
• BP6: Variant 5-58971896-A-C is Benign according to our data. Variant chr5-58971896-A-C is described in ClinVar as [Benign]. Clinvar id is 353937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.*2768T>G		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.*2768T>G		3_prime_UTR_variant	15/15	1	NM_001104631.2	ENSP00000345502
PDE4D	ENST00000507116.6	c.*2768T>G		3_prime_UTR_variant	15/15	1		ENSP00000424852	P4
PDE4D	ENST00000636120.1	c.*2768T>G		3_prime_UTR_variant	15/15	5		ENSP00000490821

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99735 AN: 151780 Hom.: 32854 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.680

GnomAD4 exome AF: 0.653 AC: 286 AN: 438 Hom.: 98 Cov.: 0 AF XY: 0.633 AC XY: 167 AN XY: 264

Gnomad4 AFR exome AF: 1.00

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.657 AC: 99793 AN: 151898 Hom.: 32871 Cov.: 31 AF XY: 0.654 AC XY: 48562 AN XY: 74208

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.724

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.678

Alfa AF: 0.681 Hom.: 35365

Bravo AF: 0.665

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 12, 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	-0.58
CADD	Benign	9.6
DANN	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs702531; hg19: chr5-58267723; COSMIC: COSV57717084; COSMIC: COSV57717084;