rs10838708

Variant names:

• chr11-47419962-G-A
• rs10838708
• NM_002804.5:c.1127+302C>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.1127+302C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 151,976 control chromosomes in the GnomAD database, including 12,358 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 0.39 (12358 hom., cov: 31)
• Consequence: PSMC3 NM_002804.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• Publications: 43 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002804.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC3	NM_002804.5	MANE Select	c.1127+302C>T		intron	N/A	NP_002795.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC3	ENST00000298852.8	TSL:1 MANE Select	c.1127+302C>T		intron	N/A	ENSP00000298852.3
	PSMC3	ENST00000619920.4	TSL:1	c.1127+302C>T		intron	N/A	ENSP00000481029.1
	PSMC3	ENST00000602866.5	TSL:1	c.1079+302C>T		intron	N/A	ENSP00000473652.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58759 AN: 151860 Hom.: 12347 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.416

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.387 AC: 58798 AN: 151976 Hom.: 12358 Cov.: 31 AF XY: 0.384 AC XY: 28535 AN XY: 74252

African (AFR) AF: 0.223 AC: 9246 AN: 41468

American (AMR) AF: 0.457 AC: 6970 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1503 AN: 3460

East Asian (EAS) AF: 0.262 AC: 1353 AN: 5164

South Asian (SAS) AF: 0.340 AC: 1639 AN: 4814

European-Finnish (FIN) AF: 0.431 AC: 4549 AN: 10544

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31864 AN: 67946

Other (OTH) AF: 0.423 AC: 895 AN: 2114

Alfa AF: 0.438 Hom.: 48291

Bravo AF: 0.382

Asia WGS AF: 0.311 AC: 1090 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.41
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs10838708; hg19: chr11-47441513;