rs41270492

chr6-32842188-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_148919.4(PSMB8):c.483G>A(p.Gln161=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,160 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (43 hom.)
• Consequence: PSMB8 NM_148919.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0190

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 6-32842188-C-T is Benign according to our data. Variant chr6-32842188-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 356364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32842188-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00388 (591/152364) while in subpopulation SAS AF= 0.00683 (33/4832). AF 95% confidence interval is 0.00569. There are 0 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB8	NM_148919.4	c.483G>A	p.Gln161=	synonymous_variant	4/6	ENST00000374882.8
PSMB8	NM_004159.5	c.471G>A	p.Gln157=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.483G>A	p.Gln161=	synonymous_variant	4/6	1	NM_148919.4	P1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00453 AC: 1119 AN: 246960 Hom.: 6 AF XY: 0.00498 AC XY: 670 AN XY: 134572

Gnomad AFR exome AF: 0.000918

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00895

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00549 AC: 8013 AN: 1460796 Hom.: 43 Cov.: 33 AF XY: 0.00578 AC XY: 4204 AN XY: 726716

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00916

Gnomad4 FIN exome AF: 0.000917

Gnomad4 NFE exome AF: 0.00588

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74504

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00617

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00524 Hom.: 5

Bravo AF: 0.00382

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PSMB8: BP4, BS2 -

Proteosome-associated autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 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
BayesDel_noAF	Benign	-0.35
Cadd	Benign	9.5
Dann	Benign	0.84

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

LitVar

Other links and lift over

dbSNP: rs41270492; hg19: chr6-32809965;