rs241419

chr6-32856171-G-Achr6-32856171-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002800.5(PSMB9):c.94G>A(p.Val32Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0244 in 1,612,750 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (82 hom., cov: 31)
  • Exomes 𝑓: 0.024 (539 hom.)
• Consequence: PSMB9 NM_002800.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.07

Genes affected

PSMB9 (HGNC:9546): (proteasome 20S subunit beta 9) 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 located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006846845).
• BP6: Variant 6-32856171-G-A is Benign according to our data. Variant chr6-32856171-G-A is described in ClinVar as [Benign]. Clinvar id is 3056957.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0247 (3765/152264) while in subpopulation AFR AF= 0.0373 (1550/41534). AF 95% confidence interval is 0.0358. There are 82 homozygotes in gnomad4. There are 1684 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 82 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB9	NM_002800.5	c.94G>A	p.Val32Ile	missense_variant	2/6	ENST00000374859.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB9	ENST00000374859.3	c.94G>A	p.Val32Ile	missense_variant	2/6	1	NM_002800.5	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3762 AN: 152146 Hom.: 82 Cov.: 31

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0163 AC: 4020 AN: 246636 Hom.: 58 AF XY: 0.0156 AC XY: 2092 AN XY: 134396

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00662

Gnomad EAS exome AF: 0.00284

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0243 AC: 35510 AN: 1460486 Hom.: 539 Cov.: 30 AF XY: 0.0232 AC XY: 16867 AN XY: 726568

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0247 AC: 3765 AN: 152264 Hom.: 82 Cov.: 31 AF XY: 0.0226 AC XY: 1684 AN XY: 74478

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0204 Hom.: 66

Bravo AF: 0.0280

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0392 AC: 151

ESP6500AA AF: 0.0367 AC: 111

ESP6500EA AF: 0.0238 AC: 129

ExAC AF: 0.0155 AC: 1831

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0235

EpiControl AF: 0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PSMB9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.15
MPC		0.39
ClinPred		0.047	T
GERP RS		5.4
Varity_R		0.28
gMVP		0.53

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: rs241419; hg19: chr6-32823948; COSMIC: COSV100841232; COSMIC: COSV100841232;