X-55488540-G-A

Variant names:

• chrX-55488540-G-A
• rs1489541167
• NM_201286.4:c.400C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_201286.4(USP51):​c.400C>T​(p.Pro134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000333 in 899,810 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000033 (0 hom. 2 hem.)
• Consequence: USP51 NM_201286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.112

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11282551).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP51	NM_201286.4	c.400C>T	p.Pro134Ser	missense_variant	Exon 3 of 3	ENST00000500968.4	NP_958443.1
USP51	XM_017029300.2	c.400C>T	p.Pro134Ser	missense_variant	Exon 3 of 3		XP_016884789.1
USP51	XM_017029301.2	c.400C>T	p.Pro134Ser	missense_variant	Exon 2 of 2		XP_016884790.1
USP51	XM_047441870.1	c.400C>T	p.Pro134Ser	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	c.400C>T	p.Pro134Ser	missense_variant	Exon 3 of 3	1	NM_201286.4	ENSP00000423333.2
USP51	ENST00000586165.1	c.123+154C>T		intron_variant	Intron 1 of 1	1		ENSP00000490435.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000333 AC: 3 AN: 899810 Hom.: 0 Cov.: 29 AF XY: 0.00000736 AC XY: 2 AN XY: 271872

Gnomad4 AFR exome AF: 0.000109

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: 0.00000134

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>T (p.P134S) 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 400, causing the proline (P) at amino acid position 134 to be replaced by a serine (S). 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	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Uncertain	0.050	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.36		Gain of phosphorylation at P134 (P = 1e-04);
MVP		0.55
MPC		0.64
ClinPred		0.071	T
GERP RS		-0.15
Varity_R		0.041
gMVP		0.20

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: rs1489541167; hg19: chrX-55514973;