rs2297575

Positions:

• chr9-120842848-T-C

Variant summary

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

The NM_005047.4(PSMD5):​c.62A>G​(p.Glu21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,607,506 control chromosomes in the GnomAD database, including 2,416 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 0.025 (320 hom., cov: 33)
  • Exomes 𝑓: 0.017 (2096 hom.)
• Consequence: PSMD5 NM_005047.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13

Genes affected

PSMD5 (HGNC:9563): (proteasome 26S subunit, non-ATPase 5) 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. This gene encodes a non-ATPase subunit of the 19S regulator base that functions as a chaperone protein during 26S proteasome assembly. [provided by RefSeq, Jul 2012]

CUTALP (HGNC:27367): (cutA divalent cation tolerance like, pseudogene)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022414327).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD5	NM_005047.4	c.62A>G	p.Glu21Gly	missense_variant	1/10	ENST00000210313.8	NP_005038.1
PSMD5	NM_001270427.2	c.62A>G	p.Glu21Gly	missense_variant	1/9		NP_001257356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD5	ENST00000210313.8	c.62A>G	p.Glu21Gly	missense_variant	1/10	1	NM_005047.4	ENSP00000210313	P1
CUTALP	ENST00000589026.5	n.144-2145T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3820 AN: 152188 Hom.: 315 Cov.: 33

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0553 AC: 13057 AN: 236306 Hom.: 1457 AF XY: 0.0443 AC XY: 5750 AN XY: 129872

Gnomad AFR exome AF: 0.00510

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.00924

Gnomad FIN exome AF: 0.000980

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.0356

GnomAD4 exome AF: 0.0172 AC: 25051 AN: 1455200 Hom.: 2096 Cov.: 31 AF XY: 0.0159 AC XY: 11503 AN XY: 723940

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.00947

Gnomad4 FIN exome AF: 0.000984

Gnomad4 NFE exome AF: 0.00448

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0252 AC: 3838 AN: 152306 Hom.: 320 Cov.: 33 AF XY: 0.0277 AC XY: 2066 AN XY: 74466

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00437

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0147 Hom.: 109

Bravo AF: 0.0382

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00373 AC: 32

ExAC AF: 0.0431 AC: 5221

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.00029	P;P
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.4	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.037	D;D;.
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.75	P;.;.
Vest4		0.45
MPC		0.10
ClinPred		0.078	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2297575; hg19: chr9-123605126; COSMIC: COSV52959893; COSMIC: COSV52959893;