12-121915890-A-G

Variant names:

• chr12-121915890-A-G
• rs14259
• NM_002813.7:c.590A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002813.7(PSMD9):​c.590A>G​(p.Glu197Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,611,316 control chromosomes in the GnomAD database, including 74,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (6025 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68847 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 61 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013101399).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002813.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD9	NM_002813.7	MANE Select	c.590A>G	p.Glu197Gly	missense	Exon 5 of 6	NP_002804.2
	PSMD9	NM_001261400.3		c.275A>G	p.Glu92Gly	missense	Exon 3 of 4	NP_001248329.1
	PSMD9	NR_048555.3		n.445A>G		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD9	ENST00000541212.6	TSL:1 MANE Select	c.590A>G	p.Glu197Gly	missense	Exon 5 of 6	ENSP00000440485.1
	PSMD9	ENST00000537407.5	TSL:1	n.*25A>G		non_coding_transcript_exon	Exon 6 of 7	ENSP00000445058.1
	PSMD9	ENST00000537407.5	TSL:1	n.*25A>G		3_prime_UTR	Exon 6 of 7	ENSP00000445058.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38626 AN: 151850 Hom.: 6019 Cov.: 32

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.323 AC: 80685 AN: 249420 AF XY: 0.324

Gnomad AFR exome AF: 0.0695

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.502

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.301 AC: 438540 AN: 1459348 Hom.: 68847 Cov.: 33 AF XY: 0.301 AC XY: 218578 AN XY: 726050

African (AFR) AF: 0.0673 AC: 2251 AN: 33448

American (AMR) AF: 0.399 AC: 17715 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7923 AN: 26078

East Asian (EAS) AF: 0.481 AC: 19072 AN: 39670

South Asian (SAS) AF: 0.322 AC: 27685 AN: 85992

European-Finnish (FIN) AF: 0.365 AC: 19449 AN: 53352

Middle Eastern (MID) AF: 0.305 AC: 1751 AN: 5736

European-Non Finnish (NFE) AF: 0.292 AC: 324292 AN: 1110344

Other (OTH) AF: 0.305 AC: 18402 AN: 60318

GnomAD4 genome AF: 0.254 AC: 38644 AN: 151968 Hom.: 6025 Cov.: 32 AF XY: 0.261 AC XY: 19352 AN XY: 74270

African (AFR) AF: 0.0795 AC: 3300 AN: 41490

American (AMR) AF: 0.331 AC: 5041 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1028 AN: 3470

East Asian (EAS) AF: 0.501 AC: 2588 AN: 5162

South Asian (SAS) AF: 0.331 AC: 1592 AN: 4814

European-Finnish (FIN) AF: 0.366 AC: 3862 AN: 10546

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20197 AN: 67938

Other (OTH) AF: 0.283 AC: 596 AN: 2108

Alfa AF: 0.278 Hom.: 13812

Bravo AF: 0.246

TwinsUK AF: 0.281 AC: 1042

ALSPAC AF: 0.290 AC: 1119

ESP6500AA AF: 0.0742 AC: 327

ESP6500EA AF: 0.285 AC: 2448

ExAC AF: 0.317 AC: 38509

Asia WGS AF: 0.385 AC: 1334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.086
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.074
Sift	Benign	0.14	T
Sift4G	Benign	0.093	T
Polyphen		0.60	P
Vest4		0.19
MPC		0.24
ClinPred		0.041	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.55
Mutation Taster		=66/34	polymorphism (auto)

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

Other links and lift over

dbSNP: rs14259; hg19: chr12-122353796; COSMIC: COSV55838848; COSMIC: COSV55838848;