rs11540143

Variant names:

• chr6-32842170-G-A
• rs11540143
• NM_148919.4:c.501C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32842170-G-A
• chr6-32842170-G-C

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.501C>T​(p.Leu167Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,150 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (21 hom.)
• Consequence: PSMB8 NM_148919.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0150
• 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=-0.4).
• BP6: Variant 6-32842170-G-A is Benign according to our data. Variant chr6-32842170-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00221 (337/152366) while in subpopulation NFE AF = 0.00378 (257/68040). AF 95% confidence interval is 0.0034. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.501C>T	p.Leu167Leu	synonymous	Exon 4 of 6	NP_683720.2	P28062-1
	PSMB8	NM_004159.5		c.489C>T	p.Leu163Leu	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.501C>T	p.Leu167Leu	synonymous	Exon 4 of 6	ENSP00000364016.4	P28062-1
	PSMB8	ENST00000374881.3	TSL:1	c.489C>T	p.Leu163Leu	synonymous	Exon 4 of 6	ENSP00000364015.2	P28062-2
	PSMB8	ENST00000923626.1		c.507C>T	p.Leu169Leu	synonymous	Exon 4 of 6	ENSP00000593685.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00217 AC: 537 AN: 247014 AF XY: 0.00206

Gnomad AFR exome AF: 0.000590

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00631

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00318 AC: 4639 AN: 1460784 Hom.: 21 Cov.: 33 AF XY: 0.00305 AC XY: 2215 AN XY: 726706

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00673 AC: 176 AN: 26136

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.000229 AC: 12 AN: 52332

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.00367 AC: 4081 AN: 1112000

Other (OTH) AF: 0.00335 AC: 202 AN: 60386

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74522

African (AFR) AF: 0.000433 AC: 18 AN: 41582

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00352 Hom.: 0

Bravo AF: 0.00249

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (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	-0.40
CADD	Benign	7.2
DANN	Benign	0.83
PhyloP100		0.015
Mutation Taster		=92/8	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: rs11540143; hg19: chr6-32809947;