chr6-32842666-G-A

Position:

chr6-32842666-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_148919.4(PSMB8):c.407+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,608,730 control chromosomes in the GnomAD database, including 162,006 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14106 hom., cov: 32)

Exomes 𝑓: 0.45 ( 147900 hom. )

Consequence

PSMB8
NM_148919.4 splice_region, intron

Scores

Splicing: ADA: 0.00003373

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.889

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:

PSMB8 (HGNC:):

PSMB8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 6-32842666-G-A is Benign according to our data. Variant chr6-32842666-G-A is described in ClinVar as [Benign]. Clinvar id is 356365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32842666-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.407+6C>T		splice_region_variant, intron_variant		ENST00000374882.8	NP_683720.2	P28062-1X5CMJ9
PSMB8	NM_004159.5 linkuse as main transcript	c.395+6C>T		splice_region_variant, intron_variant			NP_004150.1	P28062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 linkuse as main transcript	c.407+6C>T		splice_region_variant, intron_variant		1	NM_148919.4	ENSP00000364016.4		P28062-1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65131

AN:

151960

Hom.:

14107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.397

Gnomad AMI

AF:

0.479

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.451

Gnomad OTH

AF:

0.432

GnomAD3 exomes

AF:

0.442

AC:

110896

AN:

251122

Hom.:

24756

AF XY:

0.445

AC XY:

60418

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.401

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.424

Gnomad SAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.401

Gnomad NFE exome

AF:

0.458

Gnomad OTH exome

AF:

0.441

GnomAD4 exome

AF:

0.449

AC:

654016

AN:

1456654

Hom.:

147900

Cov.:

AF XY:

0.449

AC XY:

325695

AN XY:

724976

show subpopulations

Gnomad4 AFR exome

AF:

0.400

Gnomad4 AMR exome

AF:

0.451

Gnomad4 ASJ exome

AF:

0.392

Gnomad4 EAS exome

AF:

0.392

Gnomad4 SAS exome

AF:

0.443

Gnomad4 FIN exome

AF:

0.406

Gnomad4 NFE exome

AF:

0.456

Gnomad4 OTH exome

AF:

0.451

GnomAD4 genome

AF:

0.428

AC:

65133

AN:

152076

Hom.:

14106

Cov.:

AF XY:

0.425

AC XY:

31610

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.397

Gnomad4 AMR

AF:

0.428

Gnomad4 ASJ

AF:

0.374

Gnomad4 EAS

AF:

0.425

Gnomad4 SAS

AF:

0.454

Gnomad4 FIN

AF:

0.406

Gnomad4 NFE

AF:

0.451

Gnomad4 OTH

AF:

0.427

Alfa

AF:

0.449

Hom.:

30915

Bravo

AF:

0.427

Asia WGS

AF:

0.419

AC:

1459

AN:

3478

EpiCase

AF:

0.466

EpiControl

AF:

0.469

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 14, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 64. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Proteosome-associated autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.11

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over