NM_148919.4:c.145C>A

Variant names:

• chr6-32843852-G-T
• rs2071543
• NM_148919.4:c.145C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_148919.4(PSMB8):​c.145C>A​(p.Gln49Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.133 in 1,612,468 control chromosomes in the GnomAD database, including 14,765 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1306 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13459 hom.)
• Consequence: PSMB8 NM_148919.4 missense, splice_region
• Scores: Splicing: ADA: 0.9937
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.24
• Publications: 107 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]

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-32843852-G-T is Benign according to our data. Variant chr6-32843852-G-T is described in ClinVar as Benign. ClinVar VariationId is 356368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.145C>A	p.Gln49Lys	missense_variant, splice_region_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.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	Exon 1 of 6	1	NM_148919.4	ENSP00000364016.4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19469 AN: 151988 Hom.: 1307 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.144 AC: 35259 AN: 245218 AF XY: 0.144

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.0885

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.133 AC: 194496 AN: 1460362 Hom.: 13459 Cov.: 32 AF XY: 0.133 AC XY: 96872 AN XY: 726508

African (AFR) AF: 0.109 AC: 3656 AN: 33480

American (AMR) AF: 0.191 AC: 8554 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 2308 AN: 26136

East Asian (EAS) AF: 0.161 AC: 6393 AN: 39700

South Asian (SAS) AF: 0.154 AC: 13306 AN: 86254

European-Finnish (FIN) AF: 0.124 AC: 6473 AN: 52024

Middle Eastern (MID) AF: 0.111 AC: 640 AN: 5756

European-Non Finnish (NFE) AF: 0.131 AC: 145375 AN: 1111912

Other (OTH) AF: 0.129 AC: 7791 AN: 60376

GnomAD4 genome AF: 0.128 AC: 19468 AN: 152106 Hom.: 1306 Cov.: 31 AF XY: 0.129 AC XY: 9566 AN XY: 74332

African (AFR) AF: 0.110 AC: 4580 AN: 41476

American (AMR) AF: 0.151 AC: 2315 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 290 AN: 3472

East Asian (EAS) AF: 0.183 AC: 944 AN: 5158

South Asian (SAS) AF: 0.178 AC: 856 AN: 4822

European-Finnish (FIN) AF: 0.123 AC: 1301 AN: 10588

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8755 AN: 67978

Other (OTH) AF: 0.112 AC: 236 AN: 2110

Alfa AF: 0.130 Hom.: 6142

Bravo AF: 0.129

TwinsUK AF: 0.128 AC: 473

ALSPAC AF: 0.114 AC: 439

ESP6500AA AF: 0.116 AC: 349

ESP6500EA AF: 0.133 AC: 723

ExAC AF: 0.144 AC: 16858

Asia WGS AF: 0.123 AC: 428 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.134

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 14, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11669176, 21303409, 17366619, 22037870) -

Proteasome-associated autoinflammatory syndrome 1 Benign:1

Mar 06, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome Benign:1

Jan 14, 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	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.70	D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M
PhyloP100		4.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.070
Sift	Benign	0.21	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0	.;B
Vest4		0.21
MPC		0.71
ClinPred		0.017	T
GERP RS		5.6
PromoterAI		-0.021	Neutral
Varity_R		0.18
gMVP		0.61
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.060		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: rs2071543; hg19: chr6-32811629; COSMIC: COSV62754653; COSMIC: COSV62754653;