Genetic Variant USP51:p.Pro123Leu (chrX-55488572-G-A) – 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.368C>T(p.Pro123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,037,775 control chromosomes in the GnomAD database, including 1 homozygotes. There are 298 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 1 hom. 296 hem. )

Consequence

USP51
NM_201286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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=0.1067701).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP51	NM_201286.4 link	c.368C>T	p.Pro123Leu	missense_variant	Exon 3 of 3	ENST00000500968.4	NP_958443.1	Q70EK9
USP51	XM_017029300.2 link	c.368C>T	p.Pro123Leu	missense_variant	Exon 3 of 3		XP_016884789.1	Q70EK9
USP51	XM_017029301.2 link	c.368C>T	p.Pro123Leu	missense_variant	Exon 2 of 2		XP_016884790.1	Q70EK9
USP51	XM_047441870.1 link	c.368C>T	p.Pro123Leu	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.368C>T	p.Pro123Leu	missense_variant	Exon 3 of 3	1	NM_201286.4	ENSP00000423333.2		Q70EK9
USP51	ENST00000586165.1 link	c.123+122C>T		intron_variant	Intron 1 of 1	1		ENSP00000490435.1		A0A1B0GVA6

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

110660

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33254

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000496

AC:

AN:

12093

Hom.:

AF XY:

0.00174

AC XY:

AN XY:

1149

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:

0.00122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00106

AC:

979

AN:

927115

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

296

AN XY:

285353

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:

0.00126

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000190

AC:

AN:

110660

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33254

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000635

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368C>T (p.P123L) alteration is located in exon 2 (coding exon 1) of the USP51 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a leucine (L). 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

0.096

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.53

M_CAP

Benign

0.050

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.94

REVEL

Benign

0.070

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.95

Vest4

0.24

MutPred

0.31

Loss of glycosylation at P123 (P = 0.0026);

MVP

0.068

MPC

0.64

ClinPred

0.15

GERP RS

2.3

Varity_R

0.15

gMVP

0.23

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