10-73500760-G-C

Variant names:

• chr10-73500760-G-C
• NM_001391956.1:c.4390C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001391956.1(USP54):​c.4390C>G​(p.Pro1464Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP54 NM_001391956.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

Genes affected

USP54 (HGNC:23513): (ubiquitin specific peptidase 54) Predicted to enable thiol-dependent deubiquitinase. Predicted to be involved in protein deubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

PPP3CB-AS1 (HGNC:50750): (PPP3CB antisense RNA 1 (head to head))

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001391956.1. 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
	USP54	NM_001391956.1	MANE Select	c.4390C>G	p.Pro1464Ala	missense	Exon 23 of 24	NP_001378885.1	Q70EL1-1
	USP54	NM_001391941.1		c.4456C>G	p.Pro1486Ala	missense	Exon 23 of 24	NP_001378870.1
	USP54	NM_001391953.1		c.4390C>G	p.Pro1464Ala	missense	Exon 23 of 24	NP_001378882.1	Q70EL1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP54	ENST00000687698.1	MANE Select	c.4390C>G	p.Pro1464Ala	missense	Exon 23 of 24	ENSP00000510226.1	Q70EL1-1
	USP54	ENST00000422491.7	TSL:1	c.*1461-1572C>G		intron	N/A	ENSP00000407368.4	A0A804D9U3
	PPP3CB-AS1	ENST00000422977.3	TSL:1	n.1298+1073G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450080 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721700

African (AFR) AF: 0.00 AC: 0 AN: 32458

American (AMR) AF: 0.00 AC: 0 AN: 41672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38666

South Asian (SAS) AF: 0.00 AC: 0 AN: 84886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107820

Other (OTH) AF: 0.00 AC: 0 AN: 59882

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.45		Loss of loop (P = 0.0203)
MVP		0.62
MPC		0.67
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.29
Mutation Taster		=72/28	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

hg19: chr10-75260518;