12-121915859-C-T

Variant names:

• chr12-121915859-C-T
• NM_002813.7:c.559C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002813.7(PSMD9):​c.559C>T​(p.Pro187Ser) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26974052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.559C>T	p.Pro187Ser	missense_variant	Exon 5 of 6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.244C>T	p.Pro82Ser	missense_variant	Exon 3 of 4		NP_001248329.1
PSMD9	NR_048555.3	n.414C>T		non_coding_transcript_exon_variant	Exon 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.559C>T	p.Pro187Ser	missense_variant	Exon 5 of 6	1	NM_002813.7	ENSP00000440485.1
ENSG00000256950	ENST00000546333.1	n.*86-5427C>T		intron_variant	Intron 3 of 3	5		ENSP00000477146.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.559C>T (p.P187S) alteration is located in exon 5 (coding exon 5) of the PSMD9 gene. This alteration results from a C to T substitution at nucleotide position 559, causing the proline (P) at amino acid position 187 to be replaced by a serine (S). 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	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;D
REVEL	Benign	0.066
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.83	P;.;.
Vest4		0.50
MutPred		0.33		Gain of catalytic residue at K186 (P = 0.0022);.;.;
MVP		0.33
MPC		0.26
ClinPred		0.49	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122353765;