5-77427034-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003719.5(PDE8B):c.*480T>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 0.0199 in 141,094 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (35 hom., cov: 31)
  • Exomes 𝑓: 0.013 (2 hom.)
• Consequence: PDE8B NM_003719.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.325

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=-0.86).
• BP6: Variant 5-77427034-T-G is Benign according to our data. Variant chr5-77427034-T-G is described in ClinVar as [Benign]. Clinvar id is 354188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0202 (2756/136752) while in subpopulation SAS AF= 0.0347 (142/4092). AF 95% confidence interval is 0.0301. There are 35 homozygotes in gnomad4. There are 1336 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 2757 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE8B	NM_003719.5	c.*480T>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.*480T>G		3_prime_UTR_variant	22/22	1	NM_003719.5	P1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 2757 AN: 136668 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.00641

Gnomad AMI AF: 0.0601

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0220

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.00934

Gnomad MID AF: 0.0612

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.0134 AC: 58 AN: 4342 Hom.: 2 Cov.: 0 AF XY: 0.0137 AC XY: 31 AN XY: 2264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0236

Gnomad4 FIN exome AF: 0.0577

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.0202 AC: 2756 AN: 136752 Hom.: 35 Cov.: 31 AF XY: 0.0200 AC XY: 1336 AN XY: 66772

Gnomad4 AFR AF: 0.00640

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.0220

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.0347

Gnomad4 FIN AF: 0.00934

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0262

Alfa AF: 0.0165 Hom.: 6

Bravo AF: 0.0184

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	-0.86
Cadd	Benign	1.1
Dann	Benign	0.62

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: rs72769019; hg19: chr5-76722859;