rs35100697

Variant names:

• chr6-32854255-G-A
• rs35100697
• NM_002800.5:c.26G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002800.5(PSMB9):​c.26G>A​(p.Gly9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,534,740 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0082 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (63 hom.)
• Consequence: PSMB9 NM_002800.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.36
• Publications: 5 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]

TAP1 (HGNC:43): (transporter 1, ATP binding cassette subfamily B member) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

TAP1 Gene-Disease associations (from GenCC):

• MHC class I deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• MHC class I deficiency 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041626394).
• BP6: Variant 6-32854255-G-A is Benign according to our data. Variant chr6-32854255-G-A is described in ClinVar as Benign. ClinVar VariationId is 3044101.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0082 (1249/152318) while in subpopulation AFR AF = 0.026 (1081/41574). AF 95% confidence interval is 0.0247. There are 22 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002800.5. 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
	PSMB9	NM_002800.5	MANE Select	c.26G>A	p.Gly9Glu	missense	Exon 1 of 6	NP_002791.1	P28065-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB9	ENST00000374859.3	TSL:1 MANE Select	c.26G>A	p.Gly9Glu	missense	Exon 1 of 6	ENSP00000363993.2	P28065-1
	PSMB9	ENST00000892972.1		c.26G>A	p.Gly9Glu	missense	Exon 1 of 6	ENSP00000563031.1
	PSMB9	ENST00000892971.1		c.26G>A	p.Gly9Glu	missense	Exon 1 of 5	ENSP00000563030.1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1249 AN: 152200 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00559 AC: 760 AN: 136046 AF XY: 0.00635

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00503

GnomAD4 exome AF: 0.00244 AC: 3368 AN: 1382422 Hom.: 63 Cov.: 31 AF XY: 0.00297 AC XY: 2023 AN XY: 682200

African (AFR) AF: 0.0305 AC: 929 AN: 30442

American (AMR) AF: 0.00174 AC: 55 AN: 31684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23584

East Asian (EAS) AF: 0.000198 AC: 7 AN: 35266

South Asian (SAS) AF: 0.0237 AC: 1822 AN: 76774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48010

Middle Eastern (MID) AF: 0.00219 AC: 11 AN: 5026

European-Non Finnish (NFE) AF: 0.000331 AC: 356 AN: 1074336

Other (OTH) AF: 0.00328 AC: 188 AN: 57300

GnomAD4 genome AF: 0.00820 AC: 1249 AN: 152318 Hom.: 22 Cov.: 32 AF XY: 0.00854 AC XY: 636 AN XY: 74486

African (AFR) AF: 0.0260 AC: 1081 AN: 41574

American (AMR) AF: 0.00359 AC: 55 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00476 Hom.: 6

Bravo AF: 0.00852

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0202 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00371 AC: 405

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PSMB9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.028
Sift	Benign	0.032	D
Sift4G	Benign	0.26	T
Vest4		0.23
MVP		0.40
MPC		0.53
ClinPred		0.0055	T
GERP RS		3.1
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.092
gMVP		0.59
Mutation Taster		=100/0	polymorphism

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: rs35100697; hg19: chr6-32822032; COSMIC: COSV107445381; COSMIC: COSV107445381;