9-124412374-T-C

Variant names:

• chr9-124412374-T-C
• rs1831036680
• NM_002799.4:c.373A>G

Variant summary

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

The NM_002799.4(PSMB7):​c.373A>G​(p.Met125Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PSMB7 NM_002799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

Genes affected

PSMB7 (HGNC:9544): (proteasome 20S subunit beta 7) 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. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Expression of this catalytic subunit is downregulated by gamma interferon, and proteolytic processing is required to generate a mature subunit. A pseudogene of this gene is located on the long arm of chromosome 14. [provided by RefSeq, Jul 2012]

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 rank	MANE	Protein	UniProt
PSMB7	NM_002799.4	c.373A>G	p.Met125Val	missense_variant	Exon 4 of 8	ENST00000259457.8	NP_002790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB7	ENST00000259457.8	c.373A>G	p.Met125Val	missense_variant	Exon 4 of 8	1	NM_002799.4	ENSP00000259457.3
PSMB7	ENST00000441097.1	c.373A>G	p.Met125Val	missense_variant	Exon 4 of 7	5		ENSP00000393157.1
PSMB7	ENST00000498485.5	n.490A>G		non_coding_transcript_exon_variant	Exon 4 of 7	5
PSMB7	ENST00000466951.1	n.*26A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461800 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727198

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373A>G (p.M125V) alteration is located in exon 4 (coding exon 4) of the PSMB7 gene. This alteration results from a A to G substitution at nucleotide position 373, causing the methionine (M) at amino acid position 125 to be replaced by a valine (V). 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	0.33
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.00064
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.082	T;.
Polyphen		0.63	P;.
Vest4		0.85
MutPred		0.69		Gain of catalytic residue at M125 (P = 0.0145);Gain of catalytic residue at M125 (P = 0.0145);
MVP		0.72
MPC		0.40
ClinPred		0.84	D
GERP RS		3.7
Varity_R		0.62
gMVP		0.95

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: rs1831036680; hg19: chr9-127174653;