chr6-32858467-G-A

Position:

• chr6-32858467-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_002800.5(PSMB9):​c.494G>A​(p.Gly165Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,612,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PSMB9 NM_002800.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.89

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-32858467-G-A is Pathogenic according to our data. Variant chr6-32858467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548995.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26273108). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB9	NM_002800.5	c.494G>A	p.Gly165Asp	missense_variant	5/6	ENST00000374859.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB9	ENST00000374859.3	c.494G>A	p.Gly165Asp	missense_variant	5/6	1	NM_002800.5	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000406 AC: 10 AN: 246572 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134412

Gnomad AFR exome AF: 0.000596

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460736 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726676

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74350

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000340 AC: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 27, 2022	ACMG classification criteria: PS4 supporting, PM1 moderated, PM2 moderated, PM3 supporting, BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.51	.;N
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.069
Sift	Benign	0.25	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0040	.;B
Vest4		0.69
MVP		0.50
MPC		0.53
ClinPred		0.089	T
GERP RS		4.8
Varity_R		0.51
gMVP		0.72

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: rs369359789; hg19: chr6-32826244;