4-119248807-G-C

Variant names:

• chr4-119248807-G-C
• rs762702807
• NM_001371395.1:c.297G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3_Moderate

The NM_001371395.1(USP53):​c.297G>C​(p.Arg99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP53 NM_001371395.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.504
• Publications: 4 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_001371395.1 (USP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

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.297G>C	p.Arg99Ser	missense	Exon 7 of 19	NP_001358324.1	Q70EK8
	USP53	NM_001371399.1		c.297G>C	p.Arg99Ser	missense	Exon 5 of 17	NP_001358328.1	Q70EK8
	USP53	NM_001389658.1		c.297G>C	p.Arg99Ser	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.297G>C	p.Arg99Ser	missense	Exon 7 of 19	ENSP00000509606.1	Q70EK8
	USP53	ENST00000274030.11	TSL:1	c.297G>C	p.Arg99Ser	missense	Exon 5 of 16	ENSP00000274030.6	A0A8J9FKG6
	USP53	ENST00000509769.5	TSL:1	n.297G>C		non_coding_transcript_exon	Exon 3 of 16	ENSP00000426628.1	D6RF54

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249456 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

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: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

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: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.50
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.79		Gain of loop (P = 0.0079)
MVP		0.56
MPC		0.65
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.78
gMVP		0.79
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762702807; hg19: chr4-120169962;