Genetic Variant USP51:p.Pro139Gln (chrX-55488524-G-T) – 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.416C>A(p.Pro139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,054,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000035 ( 0 hom. 13 hem. )

Consequence

USP51
NM_201286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.422

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=0.17463446).

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.416C>A	p.Pro139Gln	missense_variant	Exon 3 of 3	ENST00000500968.4	NP_958443.1	Q70EK9
USP51	XM_017029300.2 link	c.416C>A	p.Pro139Gln	missense_variant	Exon 3 of 3		XP_016884789.1	Q70EK9
USP51	XM_017029301.2 link	c.416C>A	p.Pro139Gln	missense_variant	Exon 2 of 2		XP_016884790.1	Q70EK9
USP51	XM_047441870.1 link	c.416C>A	p.Pro139Gln	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.416C>A	p.Pro139Gln	missense_variant	Exon 3 of 3	1	NM_201286.4	ENSP00000423333.2		Q70EK9
USP51	ENST00000586165.1 link	c.123+170C>A		intron_variant	Intron 1 of 1	1		ENSP00000490435.1		A0A1B0GVA6

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

110515

Hom.:

Cov.:

AF XY:

0.0000603

AC XY:

AN XY:

33175

show subpopulations

Gnomad AFR

AF:

0.0000327

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:

0.0000573

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

943584

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

285832

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:

0.0000326

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000415

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000362

AC:

AN:

110515

Hom.:

Cov.:

AF XY:

0.0000603

AC XY:

AN XY:

33175

show subpopulations

Gnomad4 AFR

AF:

0.0000327

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:

0.0000573

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416C>A (p.P139Q) alteration is located in exon 2 (coding exon 1) of the USP51 gene. This alteration results from a C to A substitution at nucleotide position 416, causing the proline (P) at amino acid position 139 to be replaced by a glutamine (Q). 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

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.5

DANN

Benign

0.84

DEOGEN2

Benign

0.023

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.97

REVEL

Benign

0.25

Sift

Benign

0.41

Sift4G

Uncertain

0.049

Polyphen

0.97

Vest4

0.22

MutPred

0.40

Loss of glycosylation at P139 (P = 5e-04);

MVP

0.47

MPC

0.58

ClinPred

0.13

GERP RS

-3.1

Varity_R

0.036

gMVP

0.15

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