20-1163153-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006814.5(PSMF1):c.575T>C(p.Val192Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00338 in 1,614,154 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (59 hom.)
• Consequence: PSMF1 NM_006814.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.83

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014114082).
• BP6: Variant 20-1163153-T-C is Benign according to our data. Variant chr20-1163153-T-C is described in ClinVar as [Benign]. Clinvar id is 785834.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2196/152306) while in subpopulation AFR AF= 0.0467 (1940/41552). AF 95% confidence interval is 0.045. There are 45 homozygotes in gnomad4. There are 1016 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMF1	NM_006814.5	c.575T>C	p.Val192Ala	missense_variant	5/7	ENST00000335877.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMF1	ENST00000335877.11	c.575T>C	p.Val192Ala	missense_variant	5/7	1	NM_006814.5	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2191 AN: 152188 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00469 AC: 1179 AN: 251366 Hom.: 27 AF XY: 0.00392 AC XY: 533 AN XY: 135854

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00223 AC: 3265 AN: 1461848 Hom.: 59 Cov.: 31 AF XY: 0.00201 AC XY: 1463 AN XY: 727230

Gnomad4 AFR exome AF: 0.0482

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.0144 AC: 2196 AN: 152306 Hom.: 45 Cov.: 32 AF XY: 0.0136 AC XY: 1016 AN XY: 74488

Gnomad4 AFR AF: 0.0467

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00431 Hom.: 15

Bravo AF: 0.0160

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0420 AC: 185

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	20
Dann	Benign	0.88
DEOGEN2	Benign	0.0044	T;T;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.065	T;T;.;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.0	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	2.4	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.91	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.23
MVP		0.13
MPC		0.088
ClinPred		0.0085	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.43

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: rs79465651; hg19: chr20-1143797;