chr16-67935680-C-T

Variant names:

• chr16-67935680-C-T
• NM_002801.4:c.401G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002801.4(PSMB10):​c.401G>A​(p.Gly134Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMB10 NM_002801.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

Genes affected

PSMB10 (HGNC:9538): (proteasome 20S subunit beta 10) 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. Proteolytic processing is required to generate a mature subunit. Expression of this gene is induced by gamma interferon, and this gene product replaces catalytic subunit 2 (proteasome beta 7 subunit) in the immunoproteasome. [provided by RefSeq, Jul 2008]

ENSG00000261884 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB10	NM_002801.4	c.401G>A	p.Gly134Asp	missense_variant	Exon 5 of 8	ENST00000358514.9	NP_002792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB10	ENST00000358514.9	c.401G>A	p.Gly134Asp	missense_variant	Exon 5 of 8	1	NM_002801.4	ENSP00000351314.4
ENSG00000261884	ENST00000573493.1	n.-41G>A		upstream_gene_variant		3		ENSP00000463376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.401G>A (p.G134D) alteration is located in exon 5 (coding exon 5) of the PSMB10 gene. This alteration results from a G to A substitution at nucleotide position 401, causing the glycine (G) at amino acid position 134 to be replaced by an aspartic acid (D). 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.2	M;.
PhyloP100		3.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;.
Vest4		0.63
MutPred		0.74		Loss of MoRF binding (P = 0.053);.;
MVP		0.78
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.86
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

hg19: chr16-67969583;