NM_002793.4:c.200A>T

Variant names:

• chr6-170549027-T-A
• NM_002793.4:c.200A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_002793.4(PSMB1):​c.200A>T​(p.Asp67Val) variant causes a missense change involving the alteration of a 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: PSMB1 NM_002793.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• Publications: 0 publications found

Genes affected

PSMB1 (HGNC:9537): (proteasome 20S subunit beta 1) 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. This gene is tightly linked to the TBP (TATA-binding protein) gene in human and in mouse, and is transcribed in the opposite orientation in both species. [provided by RefSeq, Jul 2008]

PSMB1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, hypotonia, and absent language

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.87488 (below the threshold of 3.09). Trascript score misZ: 0.6854 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with microcephaly, hypotonia, and absent language.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002793.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB1	NM_002793.4	MANE Select	c.200A>T	p.Asp67Val	missense	Exon 2 of 6	NP_002784.1	A0A140VK45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB1	ENST00000262193.7	TSL:1 MANE Select	c.200A>T	p.Asp67Val	missense	Exon 2 of 6	ENSP00000262193.6	P20618
	PSMB1	ENST00000920418.1		c.200A>T	p.Asp67Val	missense	Exon 2 of 7	ENSP00000590477.1
	PSMB1	ENST00000892690.1		c.200A>T	p.Asp67Val	missense	Exon 2 of 6	ENSP00000562749.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0081	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.40	T
Polyphen		0.89	P
Vest4		0.88
MutPred		0.61		Loss of catalytic residue at D67 (P = 0.0222)
MVP		0.82
MPC		0.52
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.77
gMVP		0.89
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr6-170858115;