rs2230681

Positions:

• chr12-121888906-T-A
• chr12-121888906-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002813.7(PSMD9):​c.50T>A​(p.Val17Asp) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V17A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055524558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.50T>A	p.Val17Asp	missense_variant	1/6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.50T>A	p.Val17Asp	missense_variant	1/4		NP_001248329.1
PSMD9	NR_048555.3	n.117T>A		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.50T>A	p.Val17Asp	missense_variant	1/6	1	NM_002813.7	ENSP00000440485	P4

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1444668 Hom.: 0 Cov.: 64 AF XY: 0.00 AC XY: 0 AN XY: 717186

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.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.2
DANN	Benign	0.77
DEOGEN2	Benign	0.0084	T;T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.51	T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.090	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D;D;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.080
MutPred		0.32		Gain of catalytic residue at V18 (P = 0.0038);Gain of catalytic residue at V18 (P = 0.0038);Gain of catalytic residue at V18 (P = 0.0038);Gain of catalytic residue at V18 (P = 0.0038);
MVP		0.067
MPC		0.30
ClinPred		0.083	T
GERP RS		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.24

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: rs2230681; hg19: chr12-122326812;