1-151399588-A-C

Variant names:

• chr1-151399588-A-C
• rs756993675
• NM_002796.3:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_002796.3(PSMB4):​c.1A>C​(p.Met1?) variant causes a initiator codon change. 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: 31)
• Consequence: PSMB4 NM_002796.3 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

Genes affected

PSMB4 (HGNC:9541): (proteasome 20S subunit beta 4) 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. [provided by RefSeq, Jul 2008]

PSMB4 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 3

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

ENSG00000307595 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 32 codons. Genomic position: 151399681. Lost 0.118 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002796.3. 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
	PSMB4	NM_002796.3	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 7	NP_002787.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB4	ENST00000290541.7	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 7	ENSP00000290541.6	P28070
	PSMB4	ENST00000933662.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000603721.1
	PSMB4	ENST00000933663.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000603722.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
PhyloP100		4.8
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.52	P
Vest4		0.81
MutPred		0.61		Loss of catalytic residue at M1 (P = 0.0257)
MVP		0.40
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.50
Mutation Taster		=20/180	disease causing

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

Other links and lift over

dbSNP: rs756993675; hg19: chr1-151372064;