rs2293579

Positions:

• chr11-47419207-G-A
• chr11-47419207-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002804.5(PSMC3):​c.1128-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,228 control chromosomes in the GnomAD database, including 116,159 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8182 hom., cov: 32)
  • Exomes 𝑓: 0.38 (107977 hom.)
• Consequence: PSMC3 NM_002804.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003605
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.380

Genes affected

PSMC3 (HGNC:9549): (proteasome 26S subunit, ATPase 3) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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 one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMC3	NM_002804.5	c.1128-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000298852.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMC3	ENST00000298852.8	c.1128-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002804.5
PSMC3	ENST00000602866.5	c.1080-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1		P1
PSMC3	ENST00000619920.4	c.1128-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1
PSMC3	ENST00000530912.5	c.1002-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.309 AC: 47013 AN: 151950 Hom.: 8179 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.349

GnomAD3 exomes AF: 0.353 AC: 88425 AN: 250172 Hom.: 16919 AF XY: 0.369 AC XY: 49836 AN XY: 135220

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.372

Gnomad SAS exome AF: 0.488

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.379 AC: 553979 AN: 1461160 Hom.: 107977 Cov.: 39 AF XY: 0.383 AC XY: 278614 AN XY: 726932

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.412

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.381

GnomAD4 genome AF: 0.309 AC: 47021 AN: 152068 Hom.: 8182 Cov.: 32 AF XY: 0.306 AC XY: 22767 AN XY: 74344

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.477

Gnomad4 FIN AF: 0.287

Gnomad4 NFE AF: 0.388

Gnomad4 OTH AF: 0.346

Alfa AF: 0.350 Hom.: 3126

Bravo AF: 0.299

Asia WGS AF: 0.411 AC: 1430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.9
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs2293579; hg19: chr11-47440758; COSMIC: COSV54080142; COSMIC: COSV54080142;