rs41270492

Variant names:

• chr6-32842188-C-T
• rs41270492
• NM_148919.4:c.483G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_148919.4(PSMB8):​c.483G>A​(p.Gln161Gln) 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:5
• Conservation: PhyloP100: 0.0190
• Publications: 2 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 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• proteosome-associated autoinflammatory syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 356364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB8	NM_148919.4	MANE Select	c.483G>A	p.Gln161Gln	synonymous	Exon 4 of 6	NP_683720.2	P28062-1
	PSMB8	NM_004159.5		c.471G>A	p.Gln157Gln	synonymous	Exon 4 of 6	NP_004150.1	P28062-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB8	ENST00000374882.8	TSL:1 MANE Select	c.483G>A	p.Gln161Gln	synonymous	Exon 4 of 6	ENSP00000364016.4	P28062-1
	PSMB8	ENST00000374881.3	TSL:1	c.471G>A	p.Gln157Gln	synonymous	Exon 4 of 6	ENSP00000364015.2	P28062-2
	PSMB8	ENST00000923626.1		c.489G>A	p.Gln163Gln	synonymous	Exon 4 of 6	ENSP00000593685.1

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

GnomAD2 exomes AF: 0.00453 AC: 1119 AN: 246960 AF XY: 0.00498

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 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

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00329 AC: 147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00916 AC: 790 AN: 86258

European-Finnish (FIN) AF: 0.000917 AC: 48 AN: 52336

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5768

European-Non Finnish (NFE) AF: 0.00588 AC: 6537 AN: 1112008

Other (OTH) AF: 0.00487 AC: 294 AN: 60386

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

African (AFR) AF: 0.00127 AC: 53 AN: 41594

American (AMR) AF: 0.00353 AC: 54 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00617 AC: 420 AN: 68038

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00496 Hom.: 7

Bravo AF: 0.00382

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Proteasome-associated autoinflammatory syndrome 1 (1)
-	-	1	Proteosome-associated autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.5
DANN	Benign	0.84
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41270492; hg19: chr6-32809965;