14-23034812-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002797.5(PSMB5):​c.70C>A​(p.Arg24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 (0 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16404295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB5	NM_002797.5	c.70C>A	p.Arg24Ser	missense_variant	Exon 1 of 3	ENST00000361611.11	NP_002788.1
PSMB5	NM_001144932.3	c.70C>A	p.Arg24Ser	missense_variant	Exon 1 of 4		NP_001138404.1
PSMB5	NM_001130725.1	c.-112+300C>A		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>A	p.Arg24Ser	missense_variant	Exon 1 of 3	1	NM_002797.5	ENSP00000355325.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.60	T;T;D
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0060	B;P;.
Vest4		0.33
MutPred		0.48		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		0.67
MPC		1.3
ClinPred		0.74	D
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-23504021;