rs114772012

Positions:

chr6-32843975-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000374882.8(PSMB8):c.22G>A(p.Gly8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,612,242 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 51 hom., cov: 31)

Exomes 𝑓: 0.020 ( 346 hom. )

Consequence

PSMB8
ENST00000374882.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.27

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050331354).

BP6

Variant 6-32843975-C-T is Benign according to our data. Variant chr6-32843975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 356370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32843975-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0229 (3484/151888) while in subpopulation AFR AF= 0.0245 (1014/41390). AF 95% confidence interval is 0.0232. There are 51 homozygotes in gnomad4. There are 1750 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 51 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.22G>A	p.Gly8Arg	missense_variant	1/6	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5 linkuse as main transcript	c.135+304G>A		intron_variant			NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 linkuse as main transcript	c.22G>A	p.Gly8Arg	missense_variant	1/6	1	NM_148919.4	ENSP00000364016	P1	P28062-1

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3485

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0148

Gnomad FIN

AF:

0.0467

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.0192

AC:

4715

AN:

245268

Hom.:

AF XY:

0.0195

AC XY:

2610

AN XY:

134026

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.000805

Gnomad EAS exome

AF:

0.00170

Gnomad SAS exome

AF:

0.0176

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0204

AC:

29817

AN:

1460354

Hom.:

346

Cov.:

AF XY:

0.0203

AC XY:

14752

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.0260

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.000982

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.0426

Gnomad4 NFE exome

AF:

0.0210

Gnomad4 OTH exome

AF:

0.0182

GnomAD4 genome

AF:

0.0229

AC:

3484

AN:

151888

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1750

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0245

Gnomad4 AMR

AF:

0.0174

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0150

Gnomad4 FIN

AF:

0.0467

Gnomad4 NFE

AF:

0.0226

Gnomad4 OTH

AF:

0.0200

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0206

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.0268

AC:

ESP6500EA

AF:

0.0188

AC:

102

ExAC

AF:

0.0188

AC:

2223

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0215

EpiControl

AF:

0.0196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PSMB8: BS1, BS2 -

Proteasome-associated autoinflammatory syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 08, 2022	PSMB8 NM_148919.3 exon 1 p.Gly8Arg (c.22G>A): This variant has been reported in the literature in at least 1 individual with PASH (Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis) syndrome (Marzano 2014 PMID:25501066). This variant is present in 4.6% (494/10576) of Finnish alleles, including 5 homozygotes, with similar frequencies across other sub-populations in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-32843975-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:356370). Evolutionary conservation for this variant is limited, though 2 other species (squirrel and squirrel monkey) carry this variant amino acid (Arginine) as their wild type; computational predictive tools suggest that this variant may not impact the protein. In summary, this variant is not expected to cause disease and is classified as benign. -
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. -

Proteosome-associated autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;T

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.30

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.8

.;M

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.075

Sift

Uncertain

0.024

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.44

.;B

Vest4

0.14

MutPred

0.27

Gain of MoRF binding (P = 0.0023);Gain of MoRF binding (P = 0.0023);

MPC

0.67

ClinPred

0.034

GERP RS

3.9

Varity_R

0.16

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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