NM_148919.4:c.220A>T

Variant names:

• chr6-32843017-T-A
• rs17220206
• NM_148919.4:c.220A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_148919.4(PSMB8):​c.220A>T​(p.Thr74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,613,054 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T74T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (51 hom.)
• Consequence: PSMB8 NM_148919.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.20
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017019004).
• BP6: Variant 6-32843017-T-A is Benign according to our data. Variant chr6-32843017-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00748 (1139/152268) while in subpopulation AFR AF = 0.0206 (856/41546). AF 95% confidence interval is 0.0195. There are 12 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.220A>T	p.Thr74Ser	missense	Exon 2 of 6	NP_683720.2	P28062-1
	PSMB8	NM_004159.5		c.208A>T	p.Thr70Ser	missense	Exon 2 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.220A>T	p.Thr74Ser	missense	Exon 2 of 6	ENSP00000364016.4	P28062-1
	PSMB8	ENST00000374881.3	TSL:1	c.208A>T	p.Thr70Ser	missense	Exon 2 of 6	ENSP00000364015.2	P28062-2
	PSMB8	ENST00000923626.1		c.220A>T	p.Thr74Ser	missense	Exon 2 of 6	ENSP00000593685.1

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1140 AN: 152150 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00450 AC: 1111 AN: 246864 AF XY: 0.00498

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00153

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00266 AC: 3888 AN: 1460786 Hom.: 51 Cov.: 33 AF XY: 0.00304 AC XY: 2209 AN XY: 726708

African (AFR) AF: 0.0214 AC: 716 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.000856 AC: 34 AN: 39700

South Asian (SAS) AF: 0.0150 AC: 1295 AN: 86258

European-Finnish (FIN) AF: 0.0000573 AC: 3 AN: 52324

Middle Eastern (MID) AF: 0.0166 AC: 96 AN: 5768

European-Non Finnish (NFE) AF: 0.00128 AC: 1427 AN: 1112010

Other (OTH) AF: 0.00346 AC: 209 AN: 60386

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152268 Hom.: 12 Cov.: 32 AF XY: 0.00759 AC XY: 565 AN XY: 74462

African (AFR) AF: 0.0206 AC: 856 AN: 41546

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68016

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00115 Hom.: 3

Bravo AF: 0.00805

ESP6500AA AF: 0.0232 AC: 70

ESP6500EA AF: 0.00148 AC: 8

ExAC AF: 0.00495 AC: 593

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00279

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	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
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.89		Loss of sheet (P = 0.1158)
MVP		0.89
MPC		1.4
ClinPred		0.030	T
GERP RS		5.9
Varity_R		0.69
gMVP		0.85
Mutation Taster		=89/11	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: rs17220206; hg19: chr6-32810794;