6-32840819-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_148919.4(PSMB8):c.*140G>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 0.0062 in 707,190 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (39 hom.)
• Consequence: PSMB8 NM_148919.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.284

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-32840819-C-T is Benign according to our data. Variant chr6-32840819-C-T is described in ClinVar as [Benign]. Clinvar id is 904862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00406 (618/152242) while in subpopulation SAS AF= 0.0253 (122/4824). AF 95% confidence interval is 0.0216. There are 5 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB8	NM_148919.4	c.*140G>A		3_prime_UTR_variant	6/6	ENST00000374882.8
PSMB8	NM_004159.5	c.*140G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.*140G>A		3_prime_UTR_variant	6/6	1	NM_148919.4	P1

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00679 AC: 3766 AN: 554948 Hom.: 39 Cov.: 7 AF XY: 0.00793 AC XY: 2335 AN XY: 294342

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.000693

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.000529

Gnomad4 NFE exome AF: 0.00437

Gnomad4 OTH exome AF: 0.00716

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152242 Hom.: 5 Cov.: 32 AF XY: 0.00437 AC XY: 325 AN XY: 74426

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00381 Hom.: 0

Bravo AF: 0.00372

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1 Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	7.2
Dann	Benign	0.57

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: rs115433903; hg19: chr6-32808596;