rs11545172

Positions:

• chr3-184301893-G-A
• chr3-184301893-G-C

Variant summary

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

The NM_002808.5(PSMD2):​c.526G>A​(p.Ala176Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0425 in 1,614,156 control chromosomes in the GnomAD database, including 1,707 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 0.032 (131 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1576 hom.)
• Consequence: PSMD2 NM_002808.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.17

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018980205).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMD2	NM_002808.5	c.526G>A	p.Ala176Thr	missense_variant	5/21	ENST00000310118.9
PSMD2	NM_001278708.2	c.136G>A	p.Ala46Thr	missense_variant	3/19
PSMD2	NM_001278709.2	c.49G>A	p.Ala17Thr	missense_variant	3/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMD2	ENST00000310118.9	c.526G>A	p.Ala176Thr	missense_variant	5/21	1	NM_002808.5	P1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4866 AN: 152174 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0368 AC: 9261 AN: 251414 Hom.: 218 AF XY: 0.0387 AC XY: 5264 AN XY: 135910

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0443

GnomAD4 exome AF: 0.0436 AC: 63761 AN: 1461864 Hom.: 1576 Cov.: 32 AF XY: 0.0440 AC XY: 31995 AN XY: 727244

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0970

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0375

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0465

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0319 AC: 4863 AN: 152292 Hom.: 131 Cov.: 32 AF XY: 0.0322 AC XY: 2395 AN XY: 74460

Gnomad4 AFR AF: 0.00676

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0956

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0340

Alfa AF: 0.0394 Hom.: 126

Bravo AF: 0.0300

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0457 AC: 176

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0490 AC: 421

ExAC AF: 0.0365 AC: 4433

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0501

EpiControl AF: 0.0507

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.043	B;.;.
Vest4		0.10
MPC		0.67
ClinPred		0.0069	T
GERP RS		3.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.043
gMVP		0.25

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: rs11545172; hg19: chr3-184019681;