4-119239836-T-TAG

Variant names:

• chr4-119239836-T-TAG
• NM_001371395.1:c.78_79dupAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371395.1(USP53):​c.78_79dupAG​(p.Ala27GlufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP53 NM_001371395.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.181
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-119239836-T-TAG is Pathogenic according to our data. Variant chr4-119239836-T-TAG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1705629.Status of the report is criteria_provided_single_submitter, 1 stars.

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.78_79dupAG	p.Ala27GlufsTer8	frameshift	Exon 5 of 19	NP_001358324.1	Q70EK8
	USP53	NM_001371399.1		c.78_79dupAG	p.Ala27GlufsTer8	frameshift	Exon 3 of 17	NP_001358328.1	Q70EK8
	USP53	NM_001389658.1		c.78_79dupAG	p.Ala27GlufsTer8	frameshift	Exon 4 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.78_79dupAG	p.Ala27GlufsTer8	frameshift	Exon 5 of 19	ENSP00000509606.1	Q70EK8
	USP53	ENST00000274030.11	TSL:1	c.78_79dupAG	p.Ala27GlufsTer8	frameshift	Exon 3 of 16	ENSP00000274030.6	A0A8J9FKG6
	USP53	ENST00000509769.5	TSL:1	n.78_79dupAG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000426628.1	D6RF54

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr4-120160991;