chr4-119248751-A-T

Position:

• chr4-119248751-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP53	NM_001371395.1	c.241A>T	p.Ile81Leu	missense_variant	7/19	ENST00000692078.1	NP_001358324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP53	ENST00000692078.1	c.241A>T	p.Ile81Leu	missense_variant	7/19		NM_001371395.1	ENSP00000509606.1

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1369 AN: 152208 Hom.: 6 Cov.: 31

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

GnomAD3 exomes AF: 0.00936 AC: 2307 AN: 246434 Hom.: 21 AF XY: 0.00985 AC XY: 1316 AN XY: 133550

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 SAS exome AF: 0.00348

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.: 30 AF XY: 0.0121 AC XY: 8810 AN XY: 725624

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00794

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.00592

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152326 Hom.: 6 Cov.: 31 AF XY: 0.00839 AC XY: 625 AN XY: 74480

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0127 Hom.: 12

Bravo AF: 0.00935

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.000784 AC: 3

ESP6500EA AF: 0.0137 AC: 113

ExAC AF: 0.00980 AC: 1185

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	USP53: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.18	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.46	P;P
Vest4		0.47
MutPred		0.62		Gain of ubiquitination at K79 (P = 0.1215);Gain of ubiquitination at K79 (P = 0.1215);
MVP		0.53
MPC		0.16
ClinPred		0.033	T
GERP RS		6.0
Varity_R		0.085
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs113583516; hg19: chr4-120169906; COSMIC: COSV99075008;