rs1177573

chr12-121899792-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002813.7(PSMD9):c.400C>T(p.Arg134Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,614,064 control chromosomes in the GnomAD database, including 621 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 0.037 (324 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (297 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016908348).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMD9	NM_002813.7	c.400C>T	p.Arg134Trp	missense_variant	3/6	ENST00000541212.6
PSMD9	NM_001261400.3	c.139-3214C>T		intron_variant
PSMD9	NR_048555.3	n.309-3214C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMD9	ENST00000541212.6	c.400C>T	p.Arg134Trp	missense_variant	3/6	1	NM_002813.7	P4

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 5563 AN: 152218 Hom.: 323 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000749

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0100 AC: 2517 AN: 250780 Hom.: 132 AF XY: 0.00757 AC XY: 1027 AN XY: 135672

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00766

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00405 AC: 5923 AN: 1461728 Hom.: 297 Cov.: 30 AF XY: 0.00352 AC XY: 2557 AN XY: 727174

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.00917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000403

Gnomad4 OTH exome AF: 0.00949

GnomAD4 genome AF: 0.0366 AC: 5576 AN: 152336 Hom.: 324 Cov.: 33 AF XY: 0.0360 AC XY: 2681 AN XY: 74488

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0165 Hom.: 79

Bravo AF: 0.0418

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.123 AC: 544

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0122 AC: 1480

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.16
MPC		0.53
ClinPred		0.044	T
GERP RS		1.7
Varity_R		0.064
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1177573; hg19: chr12-122337698;