6-170543473-A-G

Variant names:

• chr6-170543473-A-G
• rs1474642
• NM_002793.4:c.433+128T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002793.4(PSMB1):​c.433+128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,026,384 control chromosomes in the GnomAD database, including 10,785 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1545 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9240 hom.)
• Consequence: PSMB1 NM_002793.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167
• Publications: 12 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB1	NM_002793.4	MANE Select	c.433+128T>C		intron	N/A	NP_002784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB1	ENST00000262193.7	TSL:1 MANE Select	c.433+128T>C		intron	N/A	ENSP00000262193.6
	PSMB1	ENST00000462957.1	TSL:2	n.1648+128T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19283 AN: 152042 Hom.: 1542 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.139 AC: 121173 AN: 874222 Hom.: 9240 AF XY: 0.138 AC XY: 60154 AN XY: 435714

African (AFR) AF: 0.0496 AC: 968 AN: 19502

American (AMR) AF: 0.311 AC: 6456 AN: 20772

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 2425 AN: 14714

East Asian (EAS) AF: 0.0507 AC: 1626 AN: 32084

South Asian (SAS) AF: 0.136 AC: 5242 AN: 38556

European-Finnish (FIN) AF: 0.227 AC: 8658 AN: 38078

Middle Eastern (MID) AF: 0.143 AC: 554 AN: 3878

European-Non Finnish (NFE) AF: 0.135 AC: 90069 AN: 668612

Other (OTH) AF: 0.136 AC: 5175 AN: 38026

GnomAD4 genome AF: 0.127 AC: 19291 AN: 152162 Hom.: 1545 Cov.: 32 AF XY: 0.133 AC XY: 9861 AN XY: 74384

African (AFR) AF: 0.0560 AC: 2327 AN: 41538

American (AMR) AF: 0.225 AC: 3443 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 587 AN: 3468

East Asian (EAS) AF: 0.0386 AC: 199 AN: 5160

South Asian (SAS) AF: 0.133 AC: 642 AN: 4830

European-Finnish (FIN) AF: 0.226 AC: 2383 AN: 10566

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9339 AN: 67990

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.139 Hom.: 2409

Bravo AF: 0.124

Asia WGS AF: 0.103 AC: 358 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.5
DANN	Benign	0.72
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs1474642; hg19: chr6-170852561; COSMIC: COSV51531831;