rs114772012

chr6-32843975-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 51 AR,Digenic gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.22G>A	p.Gly8Arg	missense_variant	1/6	1	NM_148919.4	P1

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

GnomAD3 exomes AF: 0.0192 AC: 4715 AN: 245268 Hom.: 69 AF XY: 0.0195 AC XY: 2610 AN XY: 134026

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

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.: 51 Cov.: 31 AF XY: 0.0236 AC XY: 1750 AN XY: 74268

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.: 39

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

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

Proteasome-associated autoinflammatory syndrome 1 Benign:2

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. -
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. -

Proteosome-associated autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	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
MutationTaster	Benign	0.99	D;D;D
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
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

Other links and lift over

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