rs1748588890

Variant names:

• chr4-119248817-G-A
• rs1748588890
• NM_001371395.1:c.307G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001371395.1(USP53):​c.307G>A​(p.Ala103Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP53 NM_001371395.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

Genes affected

USP53 (HGNC:29255): (ubiquitin specific peptidase 53) Predicted to enable thiol-dependent deubiquitinase. Predicted to be involved in response to auditory stimulus and sensory perception of sound. Predicted to act upstream of or within action potential and neuron apoptotic process. Predicted to be located in bicellular tight junction. Predicted to be active in cell-cell junction. [provided by Alliance of Genome Resources, Apr 2022]

USP53 Gene-Disease associations (from GenCC):

• cholestasis

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371395.1. 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
	USP53	NM_001371395.1	MANE Select	c.307G>A	p.Ala103Thr	missense	Exon 7 of 19	NP_001358324.1	Q70EK8
	USP53	NM_001371399.1		c.307G>A	p.Ala103Thr	missense	Exon 5 of 17	NP_001358328.1	Q70EK8
	USP53	NM_001389658.1		c.307G>A	p.Ala103Thr	missense	Exon 6 of 18	NP_001376587.1	Q70EK8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP53	ENST00000692078.1	MANE Select	c.307G>A	p.Ala103Thr	missense	Exon 7 of 19	ENSP00000509606.1	Q70EK8
	USP53	ENST00000274030.11	TSL:1	c.307G>A	p.Ala103Thr	missense	Exon 5 of 16	ENSP00000274030.6	A0A8J9FKG6
	USP53	ENST00000509769.5	TSL:1	n.307G>A		non_coding_transcript_exon	Exon 3 of 16	ENSP00000426628.1	D6RF54

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727194

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.063	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.80		Gain of glycosylation at S105 (P = 0.0528)
MVP		0.64
MPC		0.60
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.58
gMVP		0.43
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs1748588890; hg19: chr4-120169972;