X-55488636-G-A

Variant names:

• chrX-55488636-G-A
• rs1248550269
• NM_201286.4:c.304C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201286.4(USP51):​c.304C>T​(p.Arg102Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,059,792 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: USP51 NM_201286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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]

ENSG00000288739 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2129069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP51	NM_201286.4	c.304C>T	p.Arg102Cys	missense_variant	Exon 3 of 3	ENST00000500968.4	NP_958443.1
USP51	XM_017029300.2	c.304C>T	p.Arg102Cys	missense_variant	Exon 3 of 3		XP_016884789.1
USP51	XM_017029301.2	c.304C>T	p.Arg102Cys	missense_variant	Exon 2 of 2		XP_016884790.1
USP51	XM_047441870.1	c.304C>T	p.Arg102Cys	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.304C>T	p.Arg102Cys	missense_variant	Exon 3 of 3	1	NM_201286.4	ENSP00000423333.2
USP51	ENST00000586165.1	c.123+58C>T		intron_variant	Intron 1 of 1	1		ENSP00000490435.1
ENSG00000288739	ENST00000685479.1	n.-247G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000283 AC: 3 AN: 1059792 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 341666

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304C>T (p.R102C) 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 304, causing the arginine (R) at amino acid position 102 to be replaced by a cysteine (C). 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	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.076
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		0.99	D
Vest4		0.23
MutPred		0.31		Loss of MoRF binding (P = 0.0224);
MVP		0.068
MPC		0.86
ClinPred		0.58	D
GERP RS		2.6
Varity_R		0.18
gMVP		0.28

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: rs1248550269; hg19: chrX-55515069;