11-47420286-G-A

Position:

• chr11-47420286-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002804.5(PSMC3):​c.1105C>T​(p.His369Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSMC3 NM_002804.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.06

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMC3	NM_002804.5	c.1105C>T	p.His369Tyr	missense_variant	10/12	ENST00000298852.8	NP_002795.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMC3	ENST00000298852.8	c.1105C>T	p.His369Tyr	missense_variant	10/12	1	NM_002804.5	ENSP00000298852.3
PSMC3	ENST00000619920.4	c.1105C>T	p.His369Tyr	missense_variant	10/12	1		ENSP00000481029.1
PSMC3	ENST00000602866.5	c.1057C>T	p.His353Tyr	missense_variant	10/12	1		ENSP00000473652.1
PSMC3	ENST00000530912.5	c.979C>T	p.His327Tyr	missense_variant	9/11	5		ENSP00000433097.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.1105C>T (p.H369Y) alteration is located in exon 10 (coding exon 10) of the PSMC3 gene. This alteration results from a C to T substitution at nucleotide position 1105, causing the histidine (H) at amino acid position 369 to be replaced by a tyrosine (Y). 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	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;D;D;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	.;D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.99, 1.0	.;D;D;D
Vest4		0.85
MutPred		0.78		.;Loss of disorder (P = 0.0585);Loss of disorder (P = 0.0585);.;
MVP		0.87
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.97

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

Other links and lift over

dbSNP: rs2096038900; hg19: chr11-47441837;