Genetic Variant PSMB8:p.Gly8Arg (chr6-32843975-C-T) – ACMG Classification: Benign (-20 pts)

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.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
NM_148919.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.27

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 links:

PSMB9 (HGNC:9546): (proteasome 20S subunit beta 9) 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 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. [provided by RefSeq, Mar 2010]

PSMB9 links:

PSMB8-AS1 (HGNC:39758): (PSMB8 antisense RNA 1 (head to head))

PSMB8-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 6-32843975-C-T is Benign according to our data. Variant chr6-32843975-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356370.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 = 0.0229 (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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PSMB8	NM_148919.4	MANE Select	c.22G>A	p.Gly8Arg	missense	Exon 1 of 6	NP_683720.2	P28062-1
PSMB8	NM_004159.5		c.135+304G>A		intron	N/A	NP_004150.1	P28062-2
PSMB8-AS1	NR_037173.1		n.-111C>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PSMB8	ENST00000374882.8	TSL:1 MANE Select	c.22G>A	p.Gly8Arg	missense	Exon 1 of 6	ENSP00000364016.4	P28062-1
PSMB8	ENST00000374881.3	TSL:1	c.135+304G>A		intron	N/A	ENSP00000364015.2	P28062-2
PSMB8	ENST00000923626.1		c.22G>A	p.Gly8Arg	missense	Exon 1 of 6	ENSP00000593685.1

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

GnomAD2 exomes

AF:

0.0192

AC:

4715

AN:

245268

AF XY:

0.0195

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 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

African (AFR)

AF:

0.0260

AC:

871

AN:

33478

American (AMR)

AF:

0.0138

AC:

618

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000842

AC:

AN:

26130

East Asian (EAS)

AF:

0.000982

AC:

AN:

39700

South Asian (SAS)

AF:

0.0169

AC:

1460

AN:

86222

European-Finnish (FIN)

AF:

0.0426

AC:

2218

AN:

52088

Middle Eastern (MID)

AF:

0.0186

AC:

107

AN:

5768

European-Non Finnish (NFE)

AF:

0.0210

AC:

23384

AN:

1111872

Other (OTH)

AF:

0.0182

AC:

1098

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1716

3432

5147

6863

8579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.0229

AC:

3484

AN:

151888

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1750

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.0245

AC:

1014

AN:

41390

American (AMR)

AF:

0.0174

AC:

265

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.00174

AC:

AN:

5174

South Asian (SAS)

AF:

0.0150

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.0467

AC:

494

AN:

10576

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0226

AC:

1532

AN:

67920

Other (OTH)

AF:

0.0200

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

165

329

494

658

823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0198

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Proteasome-associated autoinflammatory syndrome 1 (2)

Autoinflammatory syndrome (1)

Proteosome-associated autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.30

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.8

PhyloP100

1.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

REVEL

Benign

0.075

Sift

Uncertain

0.024

Sift4G

Benign

0.11

Polyphen

0.44

Vest4

0.14

MutPred

0.27

Gain of MoRF binding (P = 0.0023)

MPC

0.67

ClinPred

0.034

GERP RS

3.9

PromoterAI

0.0032

Neutral

(source)

Varity_R

0.16

gMVP

0.70

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over