11-47420702-G-C

Variant names:

• chr11-47420702-G-C
• rs1363348500
• NM_002804.5:c.910C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_002804.5(PSMC3):​c.910C>G​(p.Arg304Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMC3 NM_002804.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.47

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 11-47420702-G-C is Pathogenic according to our data. Variant chr11-47420702-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3363101.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMC3	NM_002804.5	c.910C>G	p.Arg304Gly	missense_variant	Exon 9 of 12	ENST00000298852.8	NP_002795.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMC3	ENST00000298852.8	c.910C>G	p.Arg304Gly	missense_variant	Exon 9 of 12	1	NM_002804.5	ENSP00000298852.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PSMC3-Related Neurodevelopmental Delay Pathogenic:1

Oct 12, 2024

Molecular Genetics Laboratory, Motol Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was detected in a male proband with intellectual disability, microcephaly, global developmental delay, hyperactivity, overfriendliness, self-injurious behavior, multiple facial malformations (epicanthus, abnormality of the philthrum, hypertelorism, excessive salivation), narrow chest. This variant was found to be of a de novo origin. The variant and its clinical consequences are well documented in the study by Ebstein et al. 2023 (PMID:37256937) as it is located within the mutational hotspot in the AAA domain which was predicted to be intolerant to variations. To conclude, the variant is classified as pathogenic (ACMG PS2, PM2, PM5, PP2, PP3, PP5). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;D;D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;.;T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.4	.;L;L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	.;D;.;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	.;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Polyphen		1.0, 0.98	.;D;D;D;.
Vest4		0.74
MutPred		0.58		.;Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;.;
MVP		0.85
MPC		2.6
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1363348500; hg19: chr11-47442253;