6-32840951-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_148919.4(PSMB8):c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,609,932 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (6 hom.)
• Consequence: PSMB8 NM_148919.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0310

Genes affected

PSMB8 (HGNC:9545): (proteasome 20S subunit beta 8) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-32840951-C-T is Benign according to our data. Variant chr6-32840951-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000795 (121/152254) while in subpopulation SAS AF= 0.00311 (15/4826). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB8	NM_148919.4	c.*8G>A		3_prime_UTR_variant	6/6	ENST00000374882.8
PSMB8	NM_004159.5	c.*8G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.*8G>A		3_prime_UTR_variant	6/6	1	NM_148919.4	P1

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00109 AC: 275 AN: 251470 Hom.: 1 AF XY: 0.00111 AC XY: 151 AN XY: 135908

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000702 AC: 1024 AN: 1457678 Hom.: 6 Cov.: 30 AF XY: 0.000795 AC XY: 577 AN XY: 725390

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000556

Gnomad4 OTH exome AF: 0.000946

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74438

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000763

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1 Uncertain:1

Uncertain significance, 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, 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. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	2.8
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs376750959; hg19: chr6-32808728;