rs17220206

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 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

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

proteasome-associated autoinflammatory syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
proteosome-associated autoinflammatory syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PSMB8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 465420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4 link	c.220A>T	p.Thr74Ser	missense_variant	Exon 2 of 6	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5 link	c.208A>T	p.Thr70Ser	missense_variant	Exon 2 of 6		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 link	c.220A>T	p.Thr74Ser	missense_variant	Exon 2 of 6	1	NM_148919.4	ENSP00000364016.4

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

GnomAD2 exomes

AF:

0.00450

AC:

1111

AN:

246864

AF XY:

0.00498

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 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

African (AFR)

AF:

0.0214

AC:

716

AN:

33480

American (AMR)

AF:

0.00226

AC:

101

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26136

East Asian (EAS)

AF:

0.000856

AC:

AN:

39700

South Asian (SAS)

AF:

0.0150

AC:

1295

AN:

86258

European-Finnish (FIN)

AF:

0.0000573

AC:

AN:

52324

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00128

AC:

1427

AN:

1112010

Other (OTH)

AF:

0.00346

AC:

209

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

234

468

702

936

1170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00748

AC:

1139

AN:

152268

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0206

AC:

856

AN:

41546

American (AMR)

AF:

0.00340

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00154

AC:

AN:

5180

South Asian (SAS)

AF:

0.0133

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00198

AC:

135

AN:

68016

Other (OTH)

AF:

0.00806

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PSMB8: PM5, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Proteasome-associated autoinflammatory syndrome 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Jan 29, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

7.2

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

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over