rs12717

Positions:

• chr6-170553212-G-C
• chr6-170553212-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000262193.7(PSMB1):​c.31C>G​(p.Pro11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,611,798 control chromosomes in the GnomAD database, including 138,280 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11809 hom., cov: 34)
  • Exomes 𝑓: 0.41 (126471 hom.)
• Consequence: PSMB1 ENST00000262193.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8062194E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB1	NM_002793.4	c.31C>G	p.Pro11Ala	missense_variant	1/6	ENST00000262193.7	NP_002784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB1	ENST00000262193.7	c.31C>G	p.Pro11Ala	missense_variant	1/6	1	NM_002793.4	ENSP00000262193	P1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58105 AN: 152032 Hom.: 11787 Cov.: 34

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.389

GnomAD3 exomes AF: 0.416 AC: 103433 AN: 248614 Hom.: 22947 AF XY: 0.417 AC XY: 56112 AN XY: 134438

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.778

Gnomad SAS exome AF: 0.401

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.410 AC: 598504 AN: 1459648 Hom.: 126471 Cov.: 39 AF XY: 0.410 AC XY: 297685 AN XY: 726096

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.783

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.382 AC: 58170 AN: 152150 Hom.: 11809 Cov.: 34 AF XY: 0.387 AC XY: 28755 AN XY: 74364

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.392

Alfa AF: 0.401 Hom.: 9570

Bravo AF: 0.380

TwinsUK AF: 0.401 AC: 1487

ALSPAC AF: 0.409 AC: 1577

ESP6500AA AF: 0.297 AC: 1308

ESP6500EA AF: 0.390 AC: 3350

ExAC AF: 0.415 AC: 50443

Asia WGS AF: 0.567 AC: 1969 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.4
DANN	Benign	0.76
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.033
Sift	Benign	0.46	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.041
MPC		0.30
ClinPred		0.0031	T
GERP RS		0.41
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.055
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs12717; hg19: chr6-170862300; COSMIC: COSV51529993; COSMIC: COSV51529993;