rs9276810

Positions:

• chr6-32842666-G-A

Variant summary

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

The ENST00000374882.8(PSMB8):​c.407+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,608,730 control chromosomes in the GnomAD database, including 162,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14106 hom., cov: 32)
  • Exomes 𝑓: 0.45 (147900 hom.)
• Consequence: PSMB8 ENST00000374882.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00003373
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.889

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-32842666-G-A is Benign according to our data. Variant chr6-32842666-G-A is described in ClinVar as [Benign]. Clinvar id is 356365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32842666-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.407+6C>T		splice_donor_region_variant, intron_variant		ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5	c.395+6C>T		splice_donor_region_variant, intron_variant			NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.407+6C>T		splice_donor_region_variant, intron_variant		1	NM_148919.4	ENSP00000364016	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65131 AN: 151960 Hom.: 14107 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.432

GnomAD3 exomes AF: 0.442 AC: 110896 AN: 251122 Hom.: 24756 AF XY: 0.445 AC XY: 60418 AN XY: 135750

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.424

Gnomad SAS exome AF: 0.441

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.449 AC: 654016 AN: 1456654 Hom.: 147900 Cov.: 33 AF XY: 0.449 AC XY: 325695 AN XY: 724976

Gnomad4 AFR exome AF: 0.400

Gnomad4 AMR exome AF: 0.451

Gnomad4 ASJ exome AF: 0.392

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.428 AC: 65133 AN: 152076 Hom.: 14106 Cov.: 32 AF XY: 0.425 AC XY: 31610 AN XY: 74346

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.427

Alfa AF: 0.449 Hom.: 30915

Bravo AF: 0.427

Asia WGS AF: 0.419 AC: 1459 AN: 3478

EpiCase AF: 0.466

EpiControl AF: 0.469

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 14, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 64. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Proteosome-associated autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.11
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0040
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: rs9276810; hg19: chr6-32810443; COSMIC: COSV62753744; COSMIC: COSV62753744;