rs9357155

Variant names:

• chr6-32842071-G-A
• rs9357155
• NM_148919.4:c.537+63C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32842071-G-A
• chr6-32842071-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148919.4(PSMB8):​c.537+63C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,611,412 control chromosomes in the GnomAD database, including 12,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1037 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11347 hom.)
• Consequence: PSMB8 NM_148919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0980
• Publications: 80 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-32842071-G-A is Benign according to our data. Variant chr6-32842071-G-A is described in ClinVar as Benign. ClinVar VariationId is 1277080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.537+63C>T		intron_variant	Intron 4 of 5	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5	c.525+63C>T		intron_variant	Intron 4 of 5		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.537+63C>T		intron_variant	Intron 4 of 5	1	NM_148919.4	ENSP00000364016.4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17011 AN: 152084 Hom.: 1037 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0965

GnomAD4 exome AF: 0.122 AC: 177891 AN: 1459210 Hom.: 11347 Cov.: 33 AF XY: 0.122 AC XY: 88695 AN XY: 726046

African (AFR) AF: 0.0746 AC: 2495 AN: 33462

American (AMR) AF: 0.184 AC: 8207 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 2296 AN: 26126

East Asian (EAS) AF: 0.140 AC: 5564 AN: 39690

South Asian (SAS) AF: 0.143 AC: 12362 AN: 86214

European-Finnish (FIN) AF: 0.123 AC: 6410 AN: 52300

Middle Eastern (MID) AF: 0.0973 AC: 544 AN: 5590

European-Non Finnish (NFE) AF: 0.120 AC: 133005 AN: 1110806

Other (OTH) AF: 0.116 AC: 7008 AN: 60332

GnomAD4 genome AF: 0.112 AC: 17007 AN: 152202 Hom.: 1037 Cov.: 32 AF XY: 0.113 AC XY: 8425 AN XY: 74420

African (AFR) AF: 0.0759 AC: 3152 AN: 41538

American (AMR) AF: 0.140 AC: 2142 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.162 AC: 838 AN: 5182

South Asian (SAS) AF: 0.169 AC: 816 AN: 4822

European-Finnish (FIN) AF: 0.122 AC: 1292 AN: 10596

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8087 AN: 67986

Other (OTH) AF: 0.0945 AC: 200 AN: 2116

Alfa AF: 0.119 Hom.: 4739

Bravo AF: 0.111

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 14, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.38
PhyloP100		-0.098
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: rs9357155; hg19: chr6-32809848; COSMIC: COSV62755469; COSMIC: COSV62755469;