chr14-23034812-G-A

Variant names:

• chr14-23034812-G-A
• rs11543947
• NM_002797.5:c.70C>T

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 the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24P) has been classified as Uncertain significance.

• 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 rank	MANE	Protein	UniProt
PSMB5	NM_002797.5	c.70C>T	p.Arg24Cys	missense_variant	Exon 1 of 3	ENST00000361611.11	NP_002788.1
PSMB5	NM_001144932.3	c.70C>T	p.Arg24Cys	missense_variant	Exon 1 of 4		NP_001138404.1
PSMB5	NM_001130725.1	c.-112+300C>T		intron_variant	Intron 1 of 2		NP_001124197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB5	ENST00000361611.11	c.70C>T	p.Arg24Cys	missense_variant	Exon 1 of 3	1	NM_002797.5	ENSP00000355325.6

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;.
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;