11-47419207-G-A

Variant names:

• chr11-47419207-G-A
• rs2293579
• NM_002804.5:c.1128-10C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002804.5(PSMC3):​c.1128-10C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.0003605
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.380
• Publications: 35 publications found

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]

PSMC3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• deafness, cataract, impaired intellectual development, and polyneuropathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PSMC3	NM_002804.5	c.1128-10C>T		intron_variant	Intron 10 of 11	ENST00000298852.8	NP_002795.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMC3	ENST00000298852.8	c.1128-10C>T		intron_variant	Intron 10 of 11	1	NM_002804.5	ENSP00000298852.3
PSMC3	ENST00000619920.4	c.1128-10C>T		intron_variant	Intron 10 of 11	1		ENSP00000481029.1
PSMC3	ENST00000602866.5	c.1080-10C>T		intron_variant	Intron 10 of 11	1		ENSP00000473652.1
PSMC3	ENST00000530912.5	c.1002-10C>T		intron_variant	Intron 9 of 10	5		ENSP00000433097.1

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

GnomAD2 exomes AF: 0.353 AC: 88425 AN: 250172 AF XY: 0.369

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 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

African (AFR) AF: 0.146 AC: 4870 AN: 33466

American (AMR) AF: 0.230 AC: 10280 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10777 AN: 26128

East Asian (EAS) AF: 0.308 AC: 12211 AN: 39698

South Asian (SAS) AF: 0.479 AC: 41278 AN: 86244

European-Finnish (FIN) AF: 0.298 AC: 15884 AN: 53292

Middle Eastern (MID) AF: 0.370 AC: 2137 AN: 5768

European-Non Finnish (NFE) AF: 0.390 AC: 433566 AN: 1111468

Other (OTH) AF: 0.381 AC: 22976 AN: 60376

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

African (AFR) AF: 0.158 AC: 6567 AN: 41494

American (AMR) AF: 0.284 AC: 4345 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1432 AN: 3472

East Asian (EAS) AF: 0.365 AC: 1885 AN: 5166

South Asian (SAS) AF: 0.477 AC: 2299 AN: 4818

European-Finnish (FIN) AF: 0.287 AC: 3033 AN: 10572

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26350 AN: 67960

Other (OTH) AF: 0.346 AC: 727 AN: 2102

Alfa AF: 0.325 Hom.: 7637

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
PhyloP100		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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