rs11543947

Positions:

• chr14-23034812-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002797.5(PSMB5):​c.70C>T​(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,614,152 control chromosomes in the GnomAD database, including 4,511 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.059 (292 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4219 hom.)
• Consequence: PSMB5 NM_002797.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

Genes affected

PSMB5 (HGNC:9542): (proteasome 20S subunit beta 5) 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 in the proteasome. This catalytic subunit is not present in the immunoproteasome and is replaced by catalytic subunit 3i (proteasome beta 8 subunit). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016405582).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB5	NM_002797.5	c.70C>T	p.Arg24Cys	missense_variant	1/3	ENST00000361611.11	NP_002788.1
PSMB5	NM_001144932.3	c.70C>T	p.Arg24Cys	missense_variant	1/4		NP_001138404.1
PSMB5	NM_001130725.1	c.-112+300C>T		intron_variant			NP_001124197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB5	ENST00000361611.11	c.70C>T	p.Arg24Cys	missense_variant	1/3	1	NM_002797.5	ENSP00000355325	P1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8963 AN: 152170 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0805

Gnomad FIN AF: 0.0528

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0684

GnomAD3 exomes AF: 0.0658 AC: 16530 AN: 251248 Hom.: 694 AF XY: 0.0697 AC XY: 9468 AN XY: 135866

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.0320

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0856

Gnomad FIN exome AF: 0.0558

Gnomad NFE exome AF: 0.0795

Gnomad OTH exome AF: 0.0780

GnomAD4 exome AF: 0.0738 AC: 107851 AN: 1461864 Hom.: 4219 Cov.: 31 AF XY: 0.0749 AC XY: 54505 AN XY: 727234

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.0332

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0862

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.0771

Gnomad4 OTH exome AF: 0.0758

GnomAD4 genome AF: 0.0588 AC: 8959 AN: 152288 Hom.: 292 Cov.: 32 AF XY: 0.0580 AC XY: 4321 AN XY: 74458

Gnomad4 AFR AF: 0.0314

Gnomad4 AMR AF: 0.0461

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0801

Gnomad4 FIN AF: 0.0528

Gnomad4 NFE AF: 0.0773

Gnomad4 OTH AF: 0.0677

Alfa AF: 0.0779 Hom.: 1201

Bravo AF: 0.0566

TwinsUK AF: 0.0723 AC: 268

ALSPAC AF: 0.0771 AC: 297

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.0827 AC: 711

ExAC AF: 0.0674 AC: 8183

Asia WGS AF: 0.0350 AC: 122 AN: 3478

EpiCase AF: 0.0853

EpiControl AF: 0.0812

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N;D
REVEL	Benign	0.068
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.061	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.32
MPC		1.6
ClinPred		0.055	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.74

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: rs11543947; hg19: chr14-23504021;