Variant 6-99443599-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001346022.3(USP45):c.2039C>T(p.Ala680Val) variant causes a missense change. The variant allele was found at a frequency of 0.000638 in 1,609,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

USP45
NM_001346022.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.54

Variant links:

Genes affected

USP45 (HGNC:20080): (ubiquitin specific peptidase 45) The protein encoded by this gene is a deubiquitylase that binds ERCC1, the catalytic subunit of the XPF-ERCC1 DNA repair endonuclease. This endonuclease is a critical regulator of DNA repair processes, and the deubiquitylase activity of the encoded protein is important for maintaining the DNA repair ability of XPF-ERCC1. [provided by RefSeq, Sep 2016]

USP45 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=0.05749154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP45	NM_001346022.3 link	c.2039C>T	p.Ala680Val	missense_variant	Exon 15 of 18	ENST00000500704.7	NP_001332951.1	Q70EL2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7 link	c.2039C>T	p.Ala680Val	missense_variant	Exon 15 of 18	5	NM_001346022.3	ENSP00000424372.1		Q70EL2-1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000463

AC:

116

AN:

250620

Hom.:

AF XY:

0.000465

AC XY:

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000961

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000670

AC:

976

AN:

1457064

Hom.:

Cov.:

AF XY:

0.000633

AC XY:

459

AN XY:

724728

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

0.000207

Gnomad4 NFE exome

AF:

0.000839

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.000328

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000628

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000593

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2039C>T (p.A680V) alteration is located in exon 15 (coding exon 14) of the USP45 gene. This alteration results from a C to T substitution at nucleotide position 2039, causing the alanine (A) at amino acid position 680 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0068

T;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.057

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.010

B;B;.

Vest4

0.19

MVP

0.42

MPC

0.093

ClinPred

0.074

GERP RS

4.1

Varity_R

0.077

gMVP

0.43

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