11-47420683-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_002804.5(PSMC3):​c.929T>C​(p.Met310Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

PSMC3
NM_002804.5 missense

Scores

11
5
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.32
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PSMC3. . Gene score misZ 3.867 (greater than the threshold 3.09). Trascript score misZ 5.015 (greater than threshold 3.09). GenCC has associacion of gene with deafness, cataract, impaired intellectual development, and polyneuropathy, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
Variant 11-47420683-A-G is Pathogenic according to our data. Variant chr11-47420683-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2205821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PSMC3NM_002804.5 linkuse as main transcriptc.929T>C p.Met310Thr missense_variant 9/12 ENST00000298852.8 NP_002795.2 P17980A0A140VK42

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PSMC3ENST00000298852.8 linkuse as main transcriptc.929T>C p.Met310Thr missense_variant 9/121 NM_002804.5 ENSP00000298852.3 P17980

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2024The c.929T>C (p.M310T) alteration is located in coding exon 9 of the PSMC3 gene. This alteration results from a T to C substitution at nucleotide position 929, causing the methionine (M) at amino acid position 310 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PSMC3 c.929T>C alteration was not observed, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D;D;D;D;D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.61
T;.;T;T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Benign
1.1
.;L;L;.;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.4
.;D;.;D;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
.;D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;.
Polyphen
0.88, 0.98
.;P;P;D;.
Vest4
0.78
MutPred
0.81
.;Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;.;
MVP
0.92
MPC
2.3
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47442234; API