rs11540143

chr6-32842170-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_148919.4(PSMB8):c.501C>T(p.Leu167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,150 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (21 hom.)
• Consequence: PSMB8 NM_148919.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0150

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 6-32842170-G-A is Benign according to our data. Variant chr6-32842170-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32842170-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00221 (337/152366) while in subpopulation NFE AF= 0.00378 (257/68040). AF 95% confidence interval is 0.0034. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB8	NM_148919.4	c.501C>T	p.Leu167=	synonymous_variant	4/6	ENST00000374882.8
PSMB8	NM_004159.5	c.489C>T	p.Leu163=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.501C>T	p.Leu167=	synonymous_variant	4/6	1	NM_148919.4	P1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00217 AC: 537 AN: 247014 Hom.: 0 AF XY: 0.00206 AC XY: 277 AN XY: 134582

Gnomad AFR exome AF: 0.000590

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00631

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00318 AC: 4639 AN: 1460784 Hom.: 21 Cov.: 33 AF XY: 0.00305 AC XY: 2215 AN XY: 726706

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00673

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000229

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74522

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00352 Hom.: 0

Bravo AF: 0.00249

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PSMB8: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 16, 2018

- -

Proteasome-associated autoinflammatory syndrome 1 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 02, 2022

- -

Proteosome-associated autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	7.2
Dann	Benign	0.83

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: rs11540143; hg19: chr6-32809947;