12-121888932-C-G

Variant names:

• chr12-121888932-C-G
• NM_002813.7:c.76C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002813.7(PSMD9):​c.76C>G​(p.Leu26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

PSMD9 (HGNC:9567): (proteasome 26S subunit, non-ATPase 9) 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 a non-ATPase subunit of the 19S regulator. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ENSG00000256950 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.76C>G	p.Leu26Val	missense_variant	Exon 1 of 6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.76C>G	p.Leu26Val	missense_variant	Exon 1 of 4		NP_001248329.1
PSMD9	NR_048555.3	n.143C>G		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.76C>G	p.Leu26Val	missense_variant	Exon 1 of 6	1	NM_002813.7	ENSP00000440485.1
ENSG00000256950	ENST00000546333.1	n.76C>G		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000477146.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441826 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 715330

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76C>G (p.L26V) alteration is located in exon 1 (coding exon 1) of the PSMD9 gene. This alteration results from a C to G substitution at nucleotide position 76, causing the leucine (L) at amino acid position 26 to be replaced by a valine (V). 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	Benign	0.29
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M;.;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D;D;D;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;T
Polyphen		1.0	D;.;.;.
Vest4		0.65
MutPred		0.60		Gain of catalytic residue at V23 (P = 0.0028);Gain of catalytic residue at V23 (P = 0.0028);Gain of catalytic residue at V23 (P = 0.0028);Gain of catalytic residue at V23 (P = 0.0028);
MVP		0.44
MPC		0.68
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.77
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr12-122326838;