NM_005151.4:c.452A>G

Variant names:

• chr18-192889-A-G
• NM_005151.4:c.452A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005151.4(USP14):​c.452A>G​(p.Tyr151Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP14 NM_005151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36
• Publications: 0 publications found

Genes affected

USP14 (HGNC:12612): (ubiquitin specific peptidase 14) This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. This protein is located in the cytoplasm and cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins. Mice with a mutation that results in reduced expression of the ortholog of this protein are retarded for growth, develop severe tremors by 2 to 3 weeks of age followed by hindlimb paralysis and death by 6 to 10 weeks of age. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP14 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37356383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP14	NM_005151.4	c.452A>G	p.Tyr151Cys	missense_variant	Exon 6 of 16	ENST00000261601.8	NP_005142.1
USP14	NM_001037334.2	c.347A>G	p.Tyr116Cys	missense_variant	Exon 5 of 15		NP_001032411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP14	ENST00000261601.8	c.452A>G	p.Tyr151Cys	missense_variant	Exon 6 of 16	1	NM_005151.4	ENSP00000261601.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.452A>G (p.Y151C) alteration is located in exon 6 (coding exon 6) of the USP14 gene. This alteration results from a A to G substitution at nucleotide position 452, causing the tyrosine (Y) at amino acid position 151 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	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0016	.;.;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	.;.;.;N
PhyloP100		6.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.31	.;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.16	.;T;.;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.99	.;.;.;D
Vest4		0.50
MutPred		0.77		.;.;.;Loss of phosphorylation at Y151 (P = 0.1007);
MVP		0.30
MPC		0.77
ClinPred		0.92	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.53
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr18-192889;