rs17220206

Positions:

Variant summary

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

The NM_148919.4(PSMB8):c.220A>T(p.Thr74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,613,054 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T74T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 51 hom. )

Consequence

PSMB8
NM_148919.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.20

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=0.017019004).

BP6

Variant 6-32843017-T-A is Benign according to our data. Variant chr6-32843017-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 465420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32843017-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00748 (1139/152268) while in subpopulation AFR AF= 0.0206 (856/41546). AF 95% confidence interval is 0.0195. There are 12 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.220A>T	p.Thr74Ser	missense_variant	2/6	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5 linkuse as main transcript	c.208A>T	p.Thr70Ser	missense_variant	2/6		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 linkuse as main transcript	c.220A>T	p.Thr74Ser	missense_variant	2/6	1	NM_148919.4	ENSP00000364016	P1	P28062-1

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1140

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.00815

GnomAD3 exomes

AF:

0.00450

AC:

1111

AN:

246864

Hom.:

AF XY:

0.00498

AC XY:

670

AN XY:

134486

show subpopulations

Gnomad AFR exome

AF:

0.0209

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.00153

Gnomad SAS exome

AF:

0.0158

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00266

AC:

3888

AN:

1460786

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2209

AN XY:

726708

show subpopulations

Gnomad4 AFR exome

AF:

0.0214

Gnomad4 AMR exome

AF:

0.00226

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.000856

Gnomad4 SAS exome

AF:

0.0150

Gnomad4 FIN exome

AF:

0.0000573

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00748

AC:

1139

AN:

152268

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0206

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00805

ESP6500AA

AF:

0.0232

AC:

ESP6500EA

AF:

0.00148

AC:

ExAC

AF:

0.00495

AC:

593

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PSMB8: PM5, BS1, BS2 -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Proteasome-associated autoinflammatory syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Proteosome-associated autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 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

Pathogenic

0.70

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Uncertain

-0.033

MutationAssessor

Uncertain

2.6

.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.86

MutPred

0.89

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;

MVP

0.89

MPC

1.4

ClinPred

0.030

GERP RS

5.9

Varity_R

0.69

gMVP

0.85

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