14-23034811-C-G

Position:

• chr14-23034811-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002797.5(PSMB5):​c.71G>C​(p.Arg24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSMB5 NM_002797.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB5	NM_002797.5	c.71G>C	p.Arg24Pro	missense_variant	1/3	ENST00000361611.11	NP_002788.1
PSMB5	NM_001144932.3	c.71G>C	p.Arg24Pro	missense_variant	1/4		NP_001138404.1
PSMB5	NM_001130725.1	c.-112+301G>C		intron_variant			NP_001124197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB5	ENST00000361611.11	c.71G>C	p.Arg24Pro	missense_variant	1/3	1	NM_002797.5	ENSP00000355325.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.71G>C (p.R24P) alteration is located in exon 1 (coding exon 1) of the PSMB5 gene. This alteration results from a G to C substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;.
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.10	N;N;D
REVEL	Benign	0.095
Sift	Benign	0.21	T;T;D
Sift4G	Benign	0.28	T;T;T
Polyphen		0.16	B;P;.
Vest4		0.55
MutPred		0.47		Gain of catalytic residue at F19 (P = 2e-04);Gain of catalytic residue at F19 (P = 2e-04);Gain of catalytic residue at F19 (P = 2e-04);
MVP		0.60
MPC		1.7
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23504020;