18-199275-A-G

Position:

• chr18-199275-A-G

Variant summary

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

The NM_005151.4(USP14):​c.835A>G​(p.Ile279Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USP14 NM_005151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87

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 (HGNC:):

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/exons	MANE	Protein	UniProt
USP14	NM_005151.4	c.835A>G	p.Ile279Val	missense_variant	10/16	ENST00000261601.8	NP_005142.1
USP14	NM_001037334.2	c.730A>G	p.Ile244Val	missense_variant	9/15		NP_001032411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP14	ENST00000261601.8	c.835A>G	p.Ile279Val	missense_variant	10/16	1	NM_005151.4	ENSP00000261601.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.835A>G (p.I279V) alteration is located in exon 10 (coding exon 10) of the USP14 gene. This alteration results from a A to G substitution at nucleotide position 835, causing the isoleucine (I) at amino acid position 279 to be replaced by a valine (V). 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	.;.;.;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.95	.;N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	.;D;.;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.99	.;.;.;D
Vest4		0.49
MutPred		0.42		.;.;.;Gain of ubiquitination at K284 (P = 0.0725);
MVP		0.52
MPC		1.4
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.64
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-199275;