rs200946642

Positions:

• chr1-151399579-G-A
• chr1-151399579-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002796.3(PSMB4):​c.-9G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.002 in 1,599,106 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: PSMB4 NM_002796.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3 B:1
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB4	NM_002796.3	c.-9G>A		5_prime_UTR_variant	1/7	ENST00000290541.7	NP_002787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB4	ENST00000290541.7	c.-9G>A		5_prime_UTR_variant	1/7	1	NM_002796.3	ENSP00000290541	P1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152192 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000996 AC: 236 AN: 237036 Hom.: 0 AF XY: 0.00107 AC XY: 138 AN XY: 129264

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.00207 AC: 2992 AN: 1446914 Hom.: 6 Cov.: 30 AF XY: 0.00201 AC XY: 1445 AN XY: 719866

Gnomad4 AFR exome AF: 0.000279

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152192 Hom.: 1 Cov.: 31 AF XY: 0.00130 AC XY: 97 AN XY: 74332

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00153

EpiCase AF: 0.00240

EpiControl AF: 0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 23, 2018	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This variant occurs in a non-coding region of the PSMB4 gene. It does not change the encoded amino acid sequence of the PSMB4 protein. This variant is present in population databases (rs200946642, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome (PMID: 26524591). ClinVar contains an entry for this variant (Variation ID: 548956). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PSMB4 function (PMID: 26524591). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	- -

PSMB4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

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: rs200946642; hg19: chr1-151372055;