chr6-32844751-C-T

Variant names:

• chr6-32844751-C-T
• rs2071463
• ENST00000395330.6:c.-10+477C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000395330.6(PSMB9):​c.-10+477C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 309,492 control chromosomes in the GnomAD database, including 5,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1941 hom., cov: 32)
  • Exomes 𝑓: 0.18 (3159 hom.)
• Consequence: PSMB9 ENST00000395330.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.84
• Publications: 20 publications found

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]

PSMB8-AS1 (HGNC:39758): (PSMB8 antisense RNA 1 (head to head))

PSMB8 (HGNC:9545): (proteasome 20S subunit beta 8) 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 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]

PSMB8 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• proteosome-associated autoinflammatory syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-32844751-C-T is Benign according to our data. Variant chr6-32844751-C-T is described in ClinVar as Benign. ClinVar VariationId is 1275279.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395330.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB8-AS1	NR_037173.1		n.296C>T		non_coding_transcript_exon	Exon 2 of 3
	PSMB8-AS1	NR_037174.1		n.189+477C>T		intron	N/A
	PSMB8-AS1	NR_037175.1		n.190-59C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB9	ENST00000395330.6	TSL:3	c.-10+477C>T		intron	N/A	ENSP00000378739.1	A2ACR1
	PSMB8-AS1	ENST00000412095.1	TSL:2	n.618C>T		non_coding_transcript_exon	Exon 1 of 2
	PSMB8-AS1	ENST00000429600.2	TSL:2	n.304C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21850 AN: 152114 Hom.: 1940 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.184 AC: 28950 AN: 157260 Hom.: 3159 Cov.: 0 AF XY: 0.189 AC XY: 15647 AN XY: 82584

African (AFR) AF: 0.0471 AC: 279 AN: 5924

American (AMR) AF: 0.212 AC: 1735 AN: 8202

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 952 AN: 4836

East Asian (EAS) AF: 0.301 AC: 3097 AN: 10304

South Asian (SAS) AF: 0.244 AC: 4573 AN: 18766

European-Finnish (FIN) AF: 0.150 AC: 822 AN: 5466

Middle Eastern (MID) AF: 0.214 AC: 150 AN: 702

European-Non Finnish (NFE) AF: 0.168 AC: 15804 AN: 93934

Other (OTH) AF: 0.169 AC: 1538 AN: 9126

GnomAD4 genome AF: 0.144 AC: 21861 AN: 152232 Hom.: 1941 Cov.: 32 AF XY: 0.148 AC XY: 10992 AN XY: 74414

African (AFR) AF: 0.0468 AC: 1944 AN: 41572

American (AMR) AF: 0.204 AC: 3125 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3472

East Asian (EAS) AF: 0.266 AC: 1374 AN: 5170

South Asian (SAS) AF: 0.242 AC: 1167 AN: 4816

European-Finnish (FIN) AF: 0.149 AC: 1580 AN: 10594

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11595 AN: 68002

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.160 Hom.: 9217

Bravo AF: 0.140

Asia WGS AF: 0.285 AC: 989 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.025
DANN	Benign	0.85
PhyloP100		-3.8
PromoterAI		0.14	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2071463; hg19: chr6-32812528;