rs11545169

Positions:

• chr3-184302754-G-T

Variant summary

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

The NM_002808.5(PSMD2):​c.939G>T​(p.Glu313Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,614,012 control chromosomes in the GnomAD database, including 18,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1259 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17261 hom.)
• Consequence: PSMD2 NM_002808.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.440

Genes affected

PSMD2 (HGNC:9559): (proteasome 26S subunit ubiquitin receptor, non-ATPase 2) 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 one of the non-ATPase subunits of the 19S regulator lid. In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. A pseudogene has been identified on chromosome 1. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

PSMD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014640391).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD2	NM_002808.5	c.939G>T	p.Glu313Asp	missense_variant	7/21	ENST00000310118.9	NP_002799.3
PSMD2	NM_001278708.2	c.549G>T	p.Glu183Asp	missense_variant	5/19		NP_001265637.1
PSMD2	NM_001278709.2	c.462G>T	p.Glu154Asp	missense_variant	5/19		NP_001265638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD2	ENST00000310118.9	c.939G>T	p.Glu313Asp	missense_variant	7/21	1	NM_002808.5	ENSP00000310129.4

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17248 AN: 152010 Hom.: 1260 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.133 AC: 33536 AN: 251432 Hom.: 2543 AF XY: 0.137 AC XY: 18573 AN XY: 135892

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0269

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.150 AC: 219407 AN: 1461882 Hom.: 17261 Cov.: 35 AF XY: 0.151 AC XY: 109565 AN XY: 727242

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.113 AC: 17242 AN: 152130 Hom.: 1259 Cov.: 32 AF XY: 0.114 AC XY: 8469 AN XY: 74370

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0245

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.111

Alfa AF: 0.139 Hom.: 1890

Bravo AF: 0.103

TwinsUK AF: 0.157 AC: 582

ALSPAC AF: 0.159 AC: 613

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.161 AC: 1385

ExAC AF: 0.131 AC: 15892

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.0
DANN	Benign	0.87
DEOGEN2	Benign	0.080	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.39	N;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.87	T;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.043
MutPred		0.17		Gain of glycosylation at Y314 (P = 0.0167);.;.;
MPC		0.62
ClinPred		0.00027	T
GERP RS		1.3
Varity_R		0.17
gMVP		0.13

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: rs11545169; hg19: chr3-184020542;