20-1135276-A-G

Variant names:

• chr20-1135276-A-G
• rs2235587
• NM_006814.5:c.521A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006814.5(PSMF1):​c.521A>G​(p.His174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,294 control chromosomes in the GnomAD database, including 24,298 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (2051 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22247 hom.)
• Consequence: PSMF1 NM_006814.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 31 publications found

Genes affected

PSMF1 (HGNC:9571): (proteasome inhibitor subunit 1) 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 protein that inhibits the activation of the proteasome by the 11S and 19S regulators. Alternative transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3047457E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMF1	NM_006814.5	c.521A>G	p.His174Arg	missense_variant	Exon 4 of 7	ENST00000335877.11	NP_006805.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMF1	ENST00000335877.11	c.521A>G	p.His174Arg	missense_variant	Exon 4 of 7	1	NM_006814.5	ENSP00000338039.6

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20669 AN: 151978 Hom.: 2055 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.183 AC: 45815 AN: 250550 AF XY: 0.182

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.162 AC: 236416 AN: 1461198 Hom.: 22247 Cov.: 33 AF XY: 0.163 AC XY: 118633 AN XY: 726918

African (AFR) AF: 0.0269 AC: 901 AN: 33472

American (AMR) AF: 0.206 AC: 9191 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5092 AN: 26084

East Asian (EAS) AF: 0.492 AC: 19513 AN: 39684

South Asian (SAS) AF: 0.207 AC: 17800 AN: 86198

European-Finnish (FIN) AF: 0.165 AC: 8812 AN: 53412

Middle Eastern (MID) AF: 0.144 AC: 818 AN: 5698

European-Non Finnish (NFE) AF: 0.148 AC: 164428 AN: 1111610

Other (OTH) AF: 0.163 AC: 9861 AN: 60356

GnomAD4 genome AF: 0.136 AC: 20661 AN: 152096 Hom.: 2051 Cov.: 32 AF XY: 0.141 AC XY: 10496 AN XY: 74352

African (AFR) AF: 0.0320 AC: 1328 AN: 41508

American (AMR) AF: 0.200 AC: 3065 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 642 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2439 AN: 5148

South Asian (SAS) AF: 0.222 AC: 1065 AN: 4806

European-Finnish (FIN) AF: 0.160 AC: 1696 AN: 10600

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9977 AN: 67958

Other (OTH) AF: 0.158 AC: 333 AN: 2112

Alfa AF: 0.151 Hom.: 6231

Bravo AF: 0.136

TwinsUK AF: 0.155 AC: 574

ALSPAC AF: 0.149 AC: 574

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.150 AC: 1292

ExAC AF: 0.177 AC: 21492

Asia WGS AF: 0.281 AC: 979 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.21
DEOGEN2	Benign	0.0034	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.65	T;T;T;.
MetaRNN	Benign	0.00013	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.97	N;.;.;N
PhyloP100		1.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.75	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.038
MPC		0.089
ClinPred		0.000016	T
GERP RS		2.9
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.37
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2235587; hg19: chr20-1115919; COSMIC: COSV55676836; COSMIC: COSV55676836;