12-121915890-A-G

Position:

• chr12-121915890-A-G

Variant summary

Our verdict is Benign. Variant got -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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.590A>G	p.Glu197Gly	missense_variant	5/6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.275A>G	p.Glu92Gly	missense_variant	3/4		NP_001248329.1
PSMD9	NR_048555.3	n.445A>G		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.590A>G	p.Glu197Gly	missense_variant	5/6	1	NM_002813.7	ENSP00000440485.1
ENSG00000256950	ENST00000546333.1	n.*86-5396A>G		intron_variant		5		ENSP00000477146.1

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

GnomAD3 exomes AF: 0.323 AC: 80685 AN: 249420 Hom.: 14145 AF XY: 0.324 AC XY: 43611 AN XY: 134792

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 SAS exome AF: 0.325

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

Gnomad4 AFR exome AF: 0.0673

Gnomad4 AMR exome AF: 0.399

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.305

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

Gnomad4 AFR AF: 0.0795

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.283

Alfa AF: 0.290 Hom.: 8555

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 v4.3

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;T;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.074
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.093	T;T;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

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