20-1135221-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_006814.5(PSMF1):c.466C>T(p.Arg156Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: PSMF1 NM_006814.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.136

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010786355).
• BP6: Variant 20-1135221-C-T is Benign according to our data. Variant chr20-1135221-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 724436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMF1	NM_006814.5	c.466C>T	p.Arg156Trp	missense_variant	4/7	ENST00000335877.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMF1	ENST00000335877.11	c.466C>T	p.Arg156Trp	missense_variant	4/7	1	NM_006814.5	P1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000290 AC: 73 AN: 251434 Hom.: 0 AF XY: 0.000235 AC XY: 32 AN XY: 135894

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461868 Hom.: 2 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727236

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74454

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.086	N
LIST_S2	Uncertain	0.88	D;D;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;.;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.35
MVP		0.44
MPC		0.18
ClinPred		0.11	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146300768; hg19: chr20-1115864; COSMIC: COSV55674289; COSMIC: COSV55674289;