6-170548957-C-T

Variant names:

• chr6-170548957-C-T
• rs2076319
• NM_002793.4:c.221+49G>A

Variant summary

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

The NM_002793.4(PSMB1):​c.221+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,339,064 control chromosomes in the GnomAD database, including 185,909 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 0.58 (26370 hom., cov: 32)
  • Exomes 𝑓: 0.51 (159539 hom.)
• Consequence: PSMB1 NM_002793.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.614
• Publications: 11 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 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.221+49G>A		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.221+49G>A		intron	N/A	ENSP00000262193.6
	PSMB1	ENST00000462957.1	TSL:2	n.1436+49G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87737 AN: 151882 Hom.: 26324 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.530 AC: 120214 AN: 226740 AF XY: 0.526

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.514 AC: 610049 AN: 1187064 Hom.: 159539 Cov.: 15 AF XY: 0.513 AC XY: 308215 AN XY: 601316

African (AFR) AF: 0.759 AC: 20914 AN: 27546

American (AMR) AF: 0.460 AC: 19434 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 12836 AN: 24120

East Asian (EAS) AF: 0.791 AC: 29866 AN: 37758

South Asian (SAS) AF: 0.472 AC: 36890 AN: 78136

European-Finnish (FIN) AF: 0.481 AC: 25039 AN: 52082

Middle Eastern (MID) AF: 0.477 AC: 2474 AN: 5184

European-Non Finnish (NFE) AF: 0.501 AC: 435437 AN: 868884

Other (OTH) AF: 0.531 AC: 27159 AN: 51106

GnomAD4 genome AF: 0.578 AC: 87831 AN: 152000 Hom.: 26370 Cov.: 32 AF XY: 0.575 AC XY: 42677 AN XY: 74282

African (AFR) AF: 0.749 AC: 31037 AN: 41454

American (AMR) AF: 0.481 AC: 7355 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1765 AN: 3464

East Asian (EAS) AF: 0.785 AC: 4061 AN: 5170

South Asian (SAS) AF: 0.481 AC: 2318 AN: 4816

European-Finnish (FIN) AF: 0.486 AC: 5123 AN: 10546

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34225 AN: 67960

Other (OTH) AF: 0.561 AC: 1182 AN: 2106

Alfa AF: 0.543 Hom.: 5858

Bravo AF: 0.591

Asia WGS AF: 0.635 AC: 2205 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.40
DANN	Benign	0.57
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2076319; hg19: chr6-170858045; COSMIC: COSV51532346;