chr6-32843852-G-T

Position:

chr6-32843852-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_148919.4(PSMB8):c.145C>A(p.Gln49Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.133 in 1,612,468 control chromosomes in the GnomAD database, including 14,765 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1306 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13459 hom. )

Consequence

PSMB8
NM_148919.4 missense, splice_region

Scores

Splicing: ADA: 0.9937

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.24

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:

PSMB8 (HGNC:):

PSMB8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 6-32843852-G-T is Benign according to our data. Variant chr6-32843852-G-T is described in ClinVar as [Benign]. Clinvar id is 356368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32843852-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	1/6	ENST00000374882.8	NP_683720.2	P28062-1X5CMJ9
PSMB8	NM_004159.5 linkuse as main transcript	c.135+427C>A		intron_variant			NP_004150.1	P28062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 linkuse as main transcript	c.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	1/6	1	NM_148919.4	ENSP00000364016.4		P28062-1

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19469

AN:

151988

Hom.:

1307

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.152

Gnomad ASJ

AF:

0.0835

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.114

GnomAD3 exomes

AF:

0.144

AC:

35259

AN:

245218

Hom.:

2682

AF XY:

0.144

AC XY:

19302

AN XY:

133874

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.0885

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.133

AC:

194496

AN:

1460362

Hom.:

13459

Cov.:

AF XY:

0.133

AC XY:

96872

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.0883

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.154

Gnomad4 FIN exome

AF:

0.124

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.129

GnomAD4 genome

AF:

0.128

AC:

19468

AN:

152106

Hom.:

1306

Cov.:

AF XY:

0.129

AC XY:

9566

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.0835

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.178

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.112

Alfa

AF:

0.127

Hom.:

2886

Bravo

AF:

0.129

TwinsUK

AF:

0.128

AC:

473

ALSPAC

AF:

0.114

AC:

439

ESP6500AA

AF:

0.116

AC:

349

ESP6500EA

AF:

0.133

AC:

723

ExAC

AF:

0.144

AC:

16858

Asia WGS

AF:

0.123

AC:

428

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.134

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 11669176, 21303409, 17366619, 22037870) -

Proteasome-associated autoinflammatory syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Proteosome-associated autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.70

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

0.0010

P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.070

Sift

Benign

0.21

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.0

.;B

Vest4

0.21

MPC

0.71

ClinPred

0.017

GERP RS

5.6

Varity_R

0.18

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.060

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