6-32840951-C-T

Position:

chr6-32840951-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_148919.4(PSMB8):c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,609,932 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 6 hom. )

Consequence

PSMB8
NM_148919.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0310

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 6-32840951-C-T is Benign according to our data. Variant chr6-32840951-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000795 (121/152254) while in subpopulation SAS AF= 0.00311 (15/4826). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4 linkuse as main transcript	c.*8G>A		3_prime_UTR_variant	6/6	ENST00000374882.8	NP_683720.2	P28062-1X5CMJ9
PSMB8	NM_004159.5 linkuse as main transcript	c.*8G>A		3_prime_UTR_variant	6/6		NP_004150.1	P28062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882 linkuse as main transcript	c.*8G>A		3_prime_UTR_variant	6/6	1	NM_148919.4	ENSP00000364016.4		P28062-1

Frequencies

GnomAD3 genomes

AF:

0.000789

AC:

120

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00109

AC:

275

AN:

251470

Hom.:

AF XY:

0.00111

AC XY:

151

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00283

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000809

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000702

AC:

1024

AN:

1457678

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

577

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.000613

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.00250

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000556

Gnomad4 OTH exome

AF:

0.000946

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152254

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000472

Hom.:

Bravo

AF:

0.000763

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Proteasome-associated autoinflammatory syndrome 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.8

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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