rs2296840

Variant names:

• chr1-151399571-C-T
• rs2296840
• ENST00000933662.1:c.-17C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000933662.1(PSMB4):​c.-17C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,592,352 control chromosomes in the GnomAD database, including 8,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.079 (1308 hom., cov: 31)
  • Exomes 𝑓: 0.035 (7189 hom.)
• Consequence: PSMB4 ENST00000933662.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.680
• Publications: 13 publications found

Genes affected

PSMB4 (HGNC:9541): (proteasome 20S subunit beta 4) 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. [provided by RefSeq, Jul 2008]

PSMB4 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 3

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000307595 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-151399571-C-T is Benign according to our data. Variant chr1-151399571-C-T is described in ClinVar as Benign. ClinVar VariationId is 2637879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000933662.1. 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
	PSMB4	NM_002796.3	MANE Select	c.-17C>T		upstream_gene	N/A	NP_002787.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB4	ENST00000933662.1		c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000603721.1
	PSMB4	ENST00000933663.1		c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000603722.1
	PSMB4	ENST00000933664.1		c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000603723.1

Frequencies

GnomAD3 genomes AF: 0.0792 AC: 12052 AN: 152108 Hom.: 1303 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00369

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0977 AC: 22553 AN: 230762 AF XY: 0.0873

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.404

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.00465

Gnomad OTH exome AF: 0.0725

GnomAD4 exome AF: 0.0349 AC: 50253 AN: 1440126 Hom.: 7189 Cov.: 29 AF XY: 0.0352 AC XY: 25248 AN XY: 716294

African (AFR) AF: 0.125 AC: 3977 AN: 31832

American (AMR) AF: 0.299 AC: 11129 AN: 37160

Ashkenazi Jewish (ASJ) AF: 0.00939 AC: 235 AN: 25022

East Asian (EAS) AF: 0.453 AC: 17906 AN: 39510

South Asian (SAS) AF: 0.0884 AC: 7398 AN: 83718

European-Finnish (FIN) AF: 0.0647 AC: 3439 AN: 53192

Middle Eastern (MID) AF: 0.0207 AC: 117 AN: 5646

European-Non Finnish (NFE) AF: 0.00245 AC: 2707 AN: 1104724

Other (OTH) AF: 0.0564 AC: 3345 AN: 59322

GnomAD4 genome AF: 0.0794 AC: 12090 AN: 152226 Hom.: 1308 Cov.: 31 AF XY: 0.0864 AC XY: 6433 AN XY: 74436

African (AFR) AF: 0.117 AC: 4848 AN: 41542

American (AMR) AF: 0.211 AC: 3227 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2251 AN: 5142

South Asian (SAS) AF: 0.109 AC: 524 AN: 4822

European-Finnish (FIN) AF: 0.0758 AC: 804 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 68014

Other (OTH) AF: 0.0734 AC: 155 AN: 2112

Alfa AF: 0.0367 Hom.: 2503

Bravo AF: 0.0933

Asia WGS AF: 0.271 AC: 941 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		-0.68
PromoterAI		-0.12	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2296840; hg19: chr1-151372047; COSMIC: COSV51852063; COSMIC: COSV51852063;