Variant 18-210389-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005151.4(USP14):c.1229T>C(p.Ile410Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000416 in 1,444,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

USP14
NM_005151.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Variant links:

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 links:

USP14 (HGNC:):

USP14 links:

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ACMG classification

Classification made for transcript

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=0.10159588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP14	NM_005151.4 linkuse as main transcript	c.1229T>C	p.Ile410Thr	missense_variant	15/16	ENST00000261601.8	NP_005142.1	P54578-1
USP14	NM_001037334.2 linkuse as main transcript	c.1124T>C	p.Ile375Thr	missense_variant	14/15		NP_001032411.1	P54578-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP14	ENST00000261601.8 linkuse as main transcript	c.1229T>C	p.Ile410Thr	missense_variant	15/16	1	NM_005151.4	ENSP00000261601.6		P54578-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000416

AC:

AN:

1444020

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

718040

show subpopulations

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:

0.00000453

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.1229T>C (p.I410T) alteration is located in exon 15 (coding exon 15) of the USP14 gene. This alteration results from a T to C substitution at nucleotide position 1229, causing the isoleucine (I) at amino acid position 410 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

Benign

0.066

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.012

.;.;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.013

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

.;.;.;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.4

.;N;.;N

REVEL

Benign

0.16

Sift

Benign

0.25

.;T;.;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0010

.;.;.;B

Vest4

0.24

MVP

0.20

MPC

0.50

ClinPred

0.80

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over