Genetic Variant USP53:p.Ile81Leu (chr4-119248751-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371395.1(USP53):c.241A>T(p.Ile81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0121 in 1,611,292 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 6 hom., cov: 31)

Exomes 𝑓: 0.012 ( 160 hom. )

Consequence

USP53
NM_001371395.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.03

Publications

10 publications found

Variant links:

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)

USP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014961064).

BP6

Variant 4-119248751-A-T is Benign according to our data. Variant chr4-119248751-A-T is described in ClinVar as Benign. ClinVar VariationId is 773456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00899 (1369/152326) while in subpopulation NFE AF = 0.014 (950/68034). AF 95% confidence interval is 0.0132. There are 6 homozygotes in GnomAd4. There are 625 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP53	NM_001371395.1	MANE Select	c.241A>T	p.Ile81Leu	missense	Exon 7 of 19	NP_001358324.1	Q70EK8
USP53	NM_001371399.1		c.241A>T	p.Ile81Leu	missense	Exon 5 of 17	NP_001358328.1	Q70EK8
USP53	NM_001389658.1		c.241A>T	p.Ile81Leu	missense	Exon 6 of 18	NP_001376587.1	Q70EK8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP53	ENST00000692078.1	MANE Select	c.241A>T	p.Ile81Leu	missense	Exon 7 of 19	ENSP00000509606.1	Q70EK8
USP53	ENST00000274030.11	TSL:1	c.241A>T	p.Ile81Leu	missense	Exon 5 of 16	ENSP00000274030.6	A0A8J9FKG6
USP53	ENST00000509769.5	TSL:1	n.241A>T		non_coding_transcript_exon	Exon 3 of 16	ENSP00000426628.1	D6RF54

Frequencies

GnomAD3 genomes

AF:

0.00899

AC:

1369

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00936

AC:

2307

AN:

246434

AF XY:

0.00985

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.00768

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00460

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0124

AC:

18056

AN:

1458966

Hom.:

160

Cov.:

AF XY:

0.0121

AC XY:

8810

AN XY:

725624

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

33364

American (AMR)

AF:

0.00794

AC:

351

AN:

44196

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

362

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00392

AC:

335

AN:

85526

European-Finnish (FIN)

AF:

0.00592

AC:

316

AN:

53400

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.0143

AC:

15847

AN:

1111194

Other (OTH)

AF:

0.0121

AC:

727

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

911

1822

2732

3643

4554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00899

AC:

1369

AN:

152326

Hom.:

Cov.:

AF XY:

0.00839

AC XY:

625

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41582

American (AMR)

AF:

0.0112

AC:

171

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0140

AC:

950

AN:

68034

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0127

Hom.:

Bravo

AF:

0.00935

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.000784

AC:

ESP6500EA

AF:

0.0137

AC:

113

ExAC

AF:

0.00980

AC:

1185

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

6.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

REVEL

Benign

0.11

Sift

Benign

0.18

Sift4G

Pathogenic

0.0

Polyphen

0.46

Vest4

0.47

MutPred

0.62

Gain of ubiquitination at K79 (P = 0.1215)

MVP

0.53

MPC

0.16

ClinPred

0.033

GERP RS

6.0

Varity_R

0.085

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over