rs114772012

Variant names:

• chr6-32843975-C-T
• rs114772012
• NM_148919.4:c.22G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.27
• Publications: 9 publications found

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]

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]

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

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 6	ENST00000374882.8	NP_683720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 6	1	NM_148919.4	ENSP00000364016.4

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3485 AN: 151770 Hom.: 51 Cov.: 31

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

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.: 32 AF XY: 0.0203 AC XY: 14752 AN XY: 726508

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: 22 AN: 26130

East Asian (EAS) AF: 0.000982 AC: 39 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

GnomAD4 genome AF: 0.0229 AC: 3484 AN: 151888 Hom.: 51 Cov.: 31 AF XY: 0.0236 AC XY: 1750 AN XY: 74268

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: 3 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5174

South Asian (SAS) AF: 0.0150 AC: 72 AN: 4802

European-Finnish (FIN) AF: 0.0467 AC: 494 AN: 10576

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0226 AC: 1532 AN: 67920

Other (OTH) AF: 0.0200 AC: 42 AN: 2100

Alfa AF: 0.0198 Hom.: 54

Bravo AF: 0.0206

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.0268 AC: 81

ESP6500EA AF: 0.0188 AC: 102

ExAC AF: 0.0188 AC: 2223

Asia WGS AF: 0.00375 AC: 13 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

Submissions by phenotype

not provided Benign:3

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PSMB8: BS1, BS2 -

Proteasome-associated autoinflammatory syndrome 1 Benign:2

Aug 08, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 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	Benign	0.21
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.30	N
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	.;M
PhyloP100		1.3
PrimateAI	Uncertain	0.63	T
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	T
GERP RS		3.9
PromoterAI		0.0032	Neutral
Varity_R		0.16
gMVP		0.70
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs114772012; hg19: chr6-32811752; COSMIC: COSV62754776; COSMIC: COSV62754776;