6-32843606-A-G

Variant names:

• chr6-32843606-A-G
• rs6924102
• NM_148919.4:c.147+244T>C

Variant summary

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

The NM_148919.4(PSMB8):​c.147+244T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,006 control chromosomes in the GnomAD database, including 12,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.40 (12527 hom., cov: 32)
• Consequence: PSMB8 NM_148919.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.311
• Publications: 44 publications found

Genes affected

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: Ambry Genetics, G2P, 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=-0.88).
• BP6: Variant 6-32843606-A-G is Benign according to our data. Variant chr6-32843606-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB8	NM_148919.4	MANE Select	c.147+244T>C		intron	N/A	NP_683720.2
	PSMB8	NM_004159.5		c.136-517T>C		intron	N/A	NP_004150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB8	ENST00000374882.8	TSL:1 MANE Select	c.147+244T>C		intron	N/A	ENSP00000364016.4
	PSMB8	ENST00000374881.3	TSL:1	c.136-517T>C		intron	N/A	ENSP00000364015.2
	PSMB8	ENST00000650411.1		n.952T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61146 AN: 151888 Hom.: 12528 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.402 AC: 61150 AN: 152006 Hom.: 12527 Cov.: 32 AF XY: 0.398 AC XY: 29585 AN XY: 74284

African (AFR) AF: 0.364 AC: 15103 AN: 41456

American (AMR) AF: 0.410 AC: 6257 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3466

East Asian (EAS) AF: 0.423 AC: 2187 AN: 5170

South Asian (SAS) AF: 0.420 AC: 2027 AN: 4822

European-Finnish (FIN) AF: 0.358 AC: 3785 AN: 10560

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29098 AN: 67944

Other (OTH) AF: 0.406 AC: 858 AN: 2112

Alfa AF: 0.425 Hom.: 41783

Bravo AF: 0.403

Asia WGS AF: 0.398 AC: 1384 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.81
PhyloP100		-0.31
PromoterAI		-0.026	Neutral
Mutation Taster		=100/0	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: rs6924102; hg19: chr6-32811383;