rs9276810

Variant names:

• chr6-32842666-G-A
• rs9276810
• NM_148919.4:c.407+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148919.4(PSMB8):​c.407+6C>T variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 NM_148919.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003373
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.889
• Publications: 45 publications found

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]

PSMB8 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• proteosome-associated autoinflammatory syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 356365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.407+6C>T		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5	c.395+6C>T		splice_region_variant, intron_variant	Intron 3 of 5		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.407+6C>T		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_148919.4	ENSP00000364016.4

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

GnomAD2 exomes AF: 0.442 AC: 110896 AN: 251122 AF XY: 0.445

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 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

African (AFR) AF: 0.400 AC: 13344 AN: 33360

American (AMR) AF: 0.451 AC: 20151 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10228 AN: 26108

East Asian (EAS) AF: 0.392 AC: 15564 AN: 39682

South Asian (SAS) AF: 0.443 AC: 38188 AN: 86146

European-Finnish (FIN) AF: 0.406 AC: 21671 AN: 53392

Middle Eastern (MID) AF: 0.526 AC: 2804 AN: 5326

European-Non Finnish (NFE) AF: 0.456 AC: 504899 AN: 1107754

Other (OTH) AF: 0.451 AC: 27167 AN: 60182

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

African (AFR) AF: 0.397 AC: 16447 AN: 41462

American (AMR) AF: 0.428 AC: 6544 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1295 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2200 AN: 5172

South Asian (SAS) AF: 0.454 AC: 2187 AN: 4820

European-Finnish (FIN) AF: 0.406 AC: 4302 AN: 10584

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30654 AN: 67964

Other (OTH) AF: 0.427 AC: 902 AN: 2114

Alfa AF: 0.448 Hom.: 68505

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 14, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1 Other:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.11
DANN	Benign	0.74
PhyloP100		-0.89
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9276810; hg19: chr6-32810443; COSMIC: COSV62753744; COSMIC: COSV62753744;