4-119239763-G-A

Variant names:

• chr4-119239763-G-A
• rs1444052771
• NM_001371395.1:c.4G>A

Variant summary

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

The NM_001371395.1(USP53):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP53 NM_001371395.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

USP53 (HGNC:29255): (ubiquitin specific peptidase 53) Predicted to enable thiol-dependent deubiquitinase. Predicted to be involved in response to auditory stimulus and sensory perception of sound. Predicted to act upstream of or within action potential and neuron apoptotic process. Predicted to be located in bicellular tight junction. Predicted to be active in cell-cell junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP53	NM_001371395.1	c.4G>A	p.Ala2Thr	missense_variant	Exon 5 of 19	ENST00000692078.1	NP_001358324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP53	ENST00000692078.1	c.4G>A	p.Ala2Thr	missense_variant	Exon 5 of 19		NM_001371395.1	ENSP00000509606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454656 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723422

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4G>A (p.A2T) alteration is located in exon 4 (coding exon 1) of the USP53 gene. This alteration results from a G to A substitution at nucleotide position 4, causing the alanine (A) at amino acid position 2 to be replaced by a threonine (T). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.087	T;T
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.27		Loss of glycosylation at K5 (P = 0.0528);Loss of glycosylation at K5 (P = 0.0528);
MVP		0.78
MPC		0.58
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.65

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: rs1444052771; hg19: chr4-120160918;