rs11540143

Positions:

chr6-32842170-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0150

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.501C>T	p.Leu167=	synonymous_variant	4/6	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5 linkuse as main transcript	c.489C>T	p.Leu163=	synonymous_variant	4/6		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 linkuse as main transcript	c.501C>T	p.Leu167=	synonymous_variant	4/6	1	NM_148919.4	ENSP00000364016	P1	P28062-1

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152248

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00206

AC XY:

277

AN XY:

134582

show subpopulations

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.:

Cov.:

AF XY:

0.00305

AC XY:

2215

AN XY:

726706

show subpopulations

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.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74522

show subpopulations

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.:

Bravo

AF:

0.00249

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PSMB8: BP4 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over