rs376368459

Variant names:

• chr4-119245361-C-A
• rs376368459
• NM_001371395.1:c.169C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-119245361-C-A
• chr4-119245361-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_001371395.1(USP53):​c.169C>A​(p.Arg57Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP53 NM_001371395.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP7: Synonymous conserved (PhyloP=2.88 with no splicing effect.

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.169C>A	p.Arg57Arg	synonymous	Exon 6 of 19	NP_001358324.1	Q70EK8
	USP53	NM_001371399.1		c.169C>A	p.Arg57Arg	synonymous	Exon 4 of 17	NP_001358328.1	Q70EK8
	USP53	NM_001389658.1		c.169C>A	p.Arg57Arg	synonymous	Exon 5 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.169C>A	p.Arg57Arg	synonymous	Exon 6 of 19	ENSP00000509606.1	Q70EK8
	USP53	ENST00000274030.11	TSL:1	c.169C>A	p.Arg57Arg	synonymous	Exon 4 of 16	ENSP00000274030.6	A0A8J9FKG6
	USP53	ENST00000509769.5	TSL:1	n.169C>A		non_coding_transcript_exon	Exon 2 of 16	ENSP00000426628.1	D6RF54

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461484 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs376368459; hg19: chr4-120166516;