1-151401549-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002796.3(PSMB4):c.701T>C(p.Ile234Thr) variant causes a missense change. The variant allele was found at a frequency of 0.176 in 1,608,884 control chromosomes in the GnomAD database, including 26,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. I234I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2158 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24554 hom.)
• Consequence: PSMB4 NM_002796.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018168688).
• BP6: Variant 1-151401549-T-C is Benign according to our data. Variant chr1-151401549-T-C is described in ClinVar as [Benign]. Clinvar id is 1166562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB4	NM_002796.3	c.701T>C	p.Ile234Thr	missense_variant	6/7	ENST00000290541.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB4	ENST00000290541.7	c.701T>C	p.Ile234Thr	missense_variant	6/7	1	NM_002796.3	P1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23849 AN: 152042 Hom.: 2155 Cov.: 32

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.198 AC: 49831 AN: 251478 Hom.: 5629 AF XY: 0.196 AC XY: 26657 AN XY: 135916

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.178 AC: 259495 AN: 1456724 Hom.: 24554 Cov.: 32 AF XY: 0.179 AC XY: 129972 AN XY: 724998

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.157 AC: 23852 AN: 152160 Hom.: 2158 Cov.: 32 AF XY: 0.158 AC XY: 11772 AN XY: 74388

Gnomad4 AFR AF: 0.0876

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.160

Alfa AF: 0.178 Hom.: 6471

Bravo AF: 0.162

TwinsUK AF: 0.156 AC: 578

ALSPAC AF: 0.175 AC: 673

ESP6500AA AF: 0.0942 AC: 415

ESP6500EA AF: 0.173 AC: 1486

ExAC AF: 0.194 AC: 23508

Asia WGS AF: 0.182 AC: 632 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.176

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

PSMB4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	6.2e-7	P
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.84	P
Vest4		0.28
MPC		0.66
ClinPred		0.047	T
GERP RS		6.0
Varity_R		0.63
gMVP		0.95

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: rs4603; hg19: chr1-151374025; COSMIC: COSV51852732; COSMIC: COSV51852732;