Genetic Variant NM_148919.4:c.742+85G>T (chr6-32841446-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_148919.4(PSMB8):c.742+85G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,392,178 control chromosomes in the GnomAD database, including 111,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10304 hom., cov: 32)

Exomes 𝑓: 0.40 ( 101164 hom. )

Consequence

PSMB8
NM_148919.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0200

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 6-32841446-C-A is Benign according to our data. Variant chr6-32841446-C-A is described in ClinVar as [Benign]. Clinvar id is 1239292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4 link	c.742+85G>T		intron_variant	Intron 5 of 5	ENST00000374882.8	NP_683720.2	P28062-1X5CMJ9
PSMB8	NM_004159.5 link	c.730+85G>T		intron_variant	Intron 5 of 5		NP_004150.1	P28062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8 link	c.742+85G>T		intron_variant	Intron 5 of 5	1	NM_148919.4	ENSP00000364016.4		P28062-1

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55164

AN:

151916

Hom.:

10309

Cov.:

show subpopulations

Gnomad AFR

AF:

0.305

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.230

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.381

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.372

GnomAD4 exome

AF:

0.399

AC:

494656

AN:

1240144

Hom.:

101164

AF XY:

0.398

AC XY:

249768

AN XY:

627534

show subpopulations

Gnomad4 AFR exome

AF:

0.306

Gnomad4 AMR exome

AF:

0.300

Gnomad4 ASJ exome

AF:

0.342

Gnomad4 EAS exome

AF:

0.250

Gnomad4 SAS exome

AF:

0.333

Gnomad4 FIN exome

AF:

0.378

Gnomad4 NFE exome

AF:

0.421

Gnomad4 OTH exome

AF:

0.395

GnomAD4 genome

AF:

0.363

AC:

55156

AN:

152034

Hom.:

10304

Cov.:

AF XY:

0.358

AC XY:

26599

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.304

Gnomad4 AMR

AF:

0.323

Gnomad4 ASJ

AF:

0.327

Gnomad4 EAS

AF:

0.231

Gnomad4 SAS

AF:

0.350

Gnomad4 FIN

AF:

0.381

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.368

Alfa

AF:

0.240

Hom.:

564

Bravo

AF:

0.355

Asia WGS

AF:

0.273

AC:

951

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. 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

-0.88

CADD

Benign

2.5

DANN

Benign

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over