Variant 17-4796731-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002798.3(PSMB6):c.106A>G(p.Thr36Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,451,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

PSMB6
NM_002798.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

PSMB6 (HGNC:9543): (proteasome 20S subunit beta 6) 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. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

PSMB6 links:

PSMB6 (HGNC:):

PSMB6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB6	NM_002798.3 linkuse as main transcript	c.106A>G	p.Thr36Ala	missense_variant	2/6	ENST00000270586.8	NP_002789.1	P28072Q6IAT9
PSMB6	NM_001270481.2 linkuse as main transcript	c.106A>G	p.Thr36Ala	missense_variant	2/6		NP_001257410.1	A0A087X2I4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PSMB6	ENST00000270586.8 linkuse as main transcript	c.106A>G	p.Thr36Ala	missense_variant	2/6	1	NM_002798.3	ENSP00000270586.3	P28072
PSMB6	ENST00000614486.4 linkuse as main transcript	c.106A>G	p.Thr36Ala	missense_variant	2/6	2		ENSP00000485006.1	A0A087X2I4
PSMB6	ENST00000571309.1 linkuse as main transcript	n.97A>G		non_coding_transcript_exon_variant	2/6	3		ENSP00000460811.1	I3L3X7
PSMB6	ENST00000575079.1 linkuse as main transcript	n.140A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251066

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1451414

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

722806

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000263

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The c.106A>G (p.T36A) alteration is located in exon 2 (coding exon 2) of the PSMB6 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the threonine (T) at amino acid position 36 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

4.3

.;H

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.7

.;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.94

.;P

Vest4

0.96

MutPred

0.87

Loss of glycosylation at T36 (P = 0.0267);Loss of glycosylation at T36 (P = 0.0267);

MVP

0.82

MPC

1.3

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.99

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