chr6-170553248-G-A

Variant names:

• chr6-170553248-G-A
• rs10946279
• NM_002793.4:c.-6C>T

Variant summary

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

The NM_002793.4(PSMB1):​c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,600,360 control chromosomes in the GnomAD database, including 2,357 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 0.056 (280 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2077 hom.)
• Consequence: PSMB1 NM_002793.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 13 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 (REVEL=0.009).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB1	NM_002793.4	c.-6C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000262193.7	NP_002784.1
PSMB1	NM_002793.4	c.-6C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000262193.7	NP_002784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB1	ENST00000262193.7	c.-6C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1	NM_002793.4	ENSP00000262193.6
PSMB1	ENST00000262193.7	c.-6C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_002793.4	ENSP00000262193.6

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8509 AN: 152142 Hom.: 280 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0554

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0428 AC: 10154 AN: 237012 AF XY: 0.0413

Gnomad AFR exome AF: 0.0775

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.0775

Gnomad EAS exome AF: 0.00331

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0496 AC: 71863 AN: 1448100 Hom.: 2077 Cov.: 28 AF XY: 0.0485 AC XY: 34904 AN XY: 720358

African (AFR) AF: 0.0792 AC: 2634 AN: 33246

American (AMR) AF: 0.0371 AC: 1619 AN: 43650

Ashkenazi Jewish (ASJ) AF: 0.0792 AC: 2049 AN: 25884

East Asian (EAS) AF: 0.00399 AC: 157 AN: 39336

South Asian (SAS) AF: 0.00625 AC: 532 AN: 85084

European-Finnish (FIN) AF: 0.0331 AC: 1740 AN: 52572

Middle Eastern (MID) AF: 0.0457 AC: 249 AN: 5446

European-Non Finnish (NFE) AF: 0.0542 AC: 59832 AN: 1103110

Other (OTH) AF: 0.0510 AC: 3051 AN: 59772

GnomAD4 genome AF: 0.0559 AC: 8513 AN: 152260 Hom.: 280 Cov.: 33 AF XY: 0.0535 AC XY: 3982 AN XY: 74442

African (AFR) AF: 0.0755 AC: 3135 AN: 41534

American (AMR) AF: 0.0539 AC: 824 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5170

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10616

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0554 AC: 3770 AN: 68022

Other (OTH) AF: 0.0544 AC: 115 AN: 2114

Alfa AF: 0.0549 Hom.: 656

Bravo AF: 0.0577

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.072
DANN	Benign	0.87
PhyloP100		-1.8
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=295/5	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: rs10946279; hg19: chr6-170862336;