NM_006814.5:c.521A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006814.5(PSMF1):​c.521A>T​(p.His174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 32)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06977716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006814.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMF1	NM_006814.5	MANE Select	c.521A>T	p.His174Leu	missense	Exon 4 of 7	NP_006805.2	Q92530
	PSMF1	NM_178578.4		c.521A>T	p.His174Leu	missense	Exon 5 of 8	NP_848693.2	Q92530
	PSMF1	NM_001323408.2		c.521A>T	p.His174Leu	missense	Exon 4 of 7	NP_001310337.1	Q5QPM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMF1	ENST00000335877.11	TSL:1 MANE Select	c.521A>T	p.His174Leu	missense	Exon 4 of 7	ENSP00000338039.6	Q92530
	PSMF1	ENST00000333082.7	TSL:1	c.521A>T	p.His174Leu	missense	Exon 5 of 8	ENSP00000327704.3	Q92530
	PSMF1	ENST00000879397.1		c.521A>T	p.His174Leu	missense	Exon 4 of 8	ENSP00000549456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.057
Sift	Benign	0.032	D
Sift4G	Uncertain	0.035	D
Polyphen		0.049	B
Vest4		0.31
MutPred		0.23		Loss of solvent accessibility (P = 0.0371)
MVP		0.23
MPC		0.091
ClinPred		0.11	T
GERP RS		2.9
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.51
Mutation Taster		=96/4	polymorphism

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;