rs7172

Positions:

• chr1-151399662-G-A
• chr1-151399662-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002796.3(PSMB4):​c.75G>A​(p.Pro25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 1,613,768 control chromosomes in the GnomAD database, including 485,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (34866 hom., cov: 31)
  • Exomes 𝑓: 0.77 (450308 hom.)
• Consequence: PSMB4 NM_002796.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0750

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-151399662-G-A is Benign according to our data. Variant chr1-151399662-G-A is described in ClinVar as [Benign]. Clinvar id is 1165733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB4	NM_002796.3	c.75G>A	p.Pro25=	synonymous_variant	1/7	ENST00000290541.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB4	ENST00000290541.7	c.75G>A	p.Pro25=	synonymous_variant	1/7	1	NM_002796.3	P1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97600 AN: 151854 Hom.: 34862 Cov.: 31

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.682

GnomAD3 exomes AF: 0.665 AC: 167147 AN: 251210 Hom.: 61538 AF XY: 0.688 AC XY: 93534 AN XY: 135868

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.688

Gnomad FIN exome AF: 0.773

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.725

GnomAD4 exome AF: 0.771 AC: 1127646 AN: 1461796 Hom.: 450308 Cov.: 63 AF XY: 0.772 AC XY: 561664 AN XY: 727202

Gnomad4 AFR exome AF: 0.363

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.210

Gnomad4 SAS exome AF: 0.692

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.825

Gnomad4 OTH exome AF: 0.745

GnomAD4 genome AF: 0.642 AC: 97624 AN: 151972 Hom.: 34866 Cov.: 31 AF XY: 0.638 AC XY: 47360 AN XY: 74288

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.802

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.822

Gnomad4 OTH AF: 0.684

Alfa AF: 0.775 Hom.: 61278

Bravo AF: 0.608

Asia WGS AF: 0.507 AC: 1764 AN: 3478

EpiCase AF: 0.817

EpiControl AF: 0.819

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 79% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -

PSMB4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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

Proteasome-associated autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.0
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7172; hg19: chr1-151372138; COSMIC: COSV51850826; COSMIC: COSV51850826;