5-77427010-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003719.5(PDE8B):c.*456A>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 0.0511 in 182,122 control chromosomes in the GnomAD database, including 880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (872 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (8 hom.)
• Consequence: PDE8B NM_003719.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.403

Genes affected

PDE8B (HGNC:8794): (phosphodiesterase 8B) The protein encoded by this gene is a cyclic nucleotide phosphodiesterase (PDE) that catalyzes the hydrolysis of the second messenger cAMP. The encoded protein, which does not hydrolyze cGMP, is resistant to several PDE inhibitors. Defects in this gene are a cause of autosomal dominant striatal degeneration (ADSD). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

WDR41 (HGNC:25601): (WD repeat domain 41) Contributes to guanyl-nucleotide exchange factor activity. Involved in regulation of autophagy. Located in cytoplasm. Part of guanyl-nucleotide exchange factor complex. Colocalizes with Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-77427010-A-G is Benign according to our data. Variant chr5-77427010-A-G is described in ClinVar as [Benign]. Clinvar id is 354187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.*456A>G		3_prime_UTR_variant	22/22	ENST00000264917.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE8B	ENST00000264917.10	c.*456A>G		3_prime_UTR_variant	22/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9171 AN: 151454 Hom.: 873 Cov.: 31

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0529

GnomAD4 exome AF: 0.00409 AC: 125 AN: 30548 Hom.: 8 Cov.: 0 AF XY: 0.00365 AC XY: 57 AN XY: 15626

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00358

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000490

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0606 AC: 9186 AN: 151574 Hom.: 872 Cov.: 31 AF XY: 0.0585 AC XY: 4331 AN XY: 74084

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000844

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0523

Alfa AF: 0.0369 Hom.: 108

Bravo AF: 0.0712

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant striatal neurodegeneration type 1 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	-0.87
Cadd	Benign	5.2
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs16874261; hg19: chr5-76722835;