Variant 3-49278410-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000265560.9(USP4):c.2775T>G(p.Asp925Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

USP4
ENST00000265560.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

USP4 (HGNC:12627): (ubiquitin specific peptidase 4) The protein encoded by this gene is a protease that deubiquitinates target proteins such as ADORA2A and TRIM21. The encoded protein shuttles between the nucleus and cytoplasm and is involved in maintaining operational fidelity in the endoplasmic reticulum. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

USP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0059221983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP4	NM_003363.4 linkuse as main transcript	c.2775T>G	p.Asp925Glu	missense_variant	22/22	ENST00000265560.9	NP_003354.2
USP4	NM_199443.3 linkuse as main transcript	c.2634T>G	p.Asp878Glu	missense_variant	21/21		NP_955475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP4	ENST00000265560.9 linkuse as main transcript	c.2775T>G	p.Asp925Glu	missense_variant	22/22	1	NM_003363.4	ENSP00000265560	A1	Q13107-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251156

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000112

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000368

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000485

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

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

May 10, 2022

The c.2775T>G (p.D925E) alteration is located in exon 22 (coding exon 22) of the USP4 gene. This alteration results from a T to G substitution at nucleotide position 2775, causing the aspartic acid (D) at amino acid position 925 to be replaced by a glutamic acid (E). 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

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.29

DANN

Benign

0.90

DEOGEN2

Benign

0.033

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.81

.;L

MutationTaster

Benign

0.88

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.065

Sift

Benign

0.44

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.098

MutPred

0.22

.;Gain of glycosylation at Y928 (P = 0.0038);

MVP

0.29

MPC

0.16

ClinPred

0.0042

GERP RS

-3.8

Varity_R

0.029

gMVP

0.058

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