Genetic Variant USP51:p.Arg153Gly (chrX-55488483-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_201286.4(USP51):c.457A>G(p.Arg153Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,186,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000074 ( 0 hom. 2 hem. )

Consequence

USP51
NM_201286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.761

Variant links:

Genes affected

USP51 (HGNC:23086): (ubiquitin specific peptidase 51) Enables chromatin binding activity; histone binding activity; and thiol-dependent deubiquitinase. Involved in histone deubiquitination; regulation of cell cycle process; and regulation of double-strand break repair. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

USP51 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15769717).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP51	NM_201286.4 link	c.457A>G	p.Arg153Gly	missense_variant	Exon 3 of 3	ENST00000500968.4	NP_958443.1	Q70EK9
USP51	XM_017029300.2 link	c.457A>G	p.Arg153Gly	missense_variant	Exon 3 of 3		XP_016884789.1	Q70EK9
USP51	XM_017029301.2 link	c.457A>G	p.Arg153Gly	missense_variant	Exon 2 of 2		XP_016884790.1	Q70EK9
USP51	XM_047441870.1 link	c.457A>G	p.Arg153Gly	missense_variant	Exon 2 of 2		XP_047297826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP51	ENST00000500968.4 link	c.457A>G	p.Arg153Gly	missense_variant	Exon 3 of 3	1	NM_201286.4	ENSP00000423333.2		Q70EK9
USP51	ENST00000586165.1 link	c.123+211A>G		intron_variant	Intron 1 of 1	1		ENSP00000490435.1		A0A1B0GVA6

Frequencies

GnomAD3 genomes

AF:

0.00000905

AC:

AN:

110457

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33049

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

160502

Hom.:

AF XY:

0.00

AC XY:

AN XY:

50712

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000743

AC:

AN:

1076422

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

349362

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000964

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000905

AC:

AN:

110457

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33049

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000191

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457A>G (p.R153G) alteration is located in exon 2 (coding exon 1) of the USP51 gene. This alteration results from a A to G substitution at nucleotide position 457, causing the arginine (R) at amino acid position 153 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.020

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.51

M_CAP

Benign

0.029

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.73

REVEL

Benign

0.069

Sift

Uncertain

0.0020

Sift4G

Benign

0.13

Polyphen

0.95

Vest4

0.13

MutPred

0.27

Loss of methylation at R153 (P = 0.0124);

MVP

0.043

MPC

0.81

ClinPred

0.14

GERP RS

2.3

Varity_R

0.13

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over