Variant 6-99439801-C-T 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_001346022.3(USP45):c.2128G>A(p.Asp710Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,607,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

USP45
NM_001346022.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.29

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:

TSTD3 (HGNC:):

TSTD3 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=0.083295226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP45	NM_001346022.3 linkuse as main transcript	c.2128G>A	p.Asp710Asn	missense_variant	16/18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7 linkuse as main transcript	c.2128G>A	p.Asp710Asn	missense_variant	16/18	5	NM_001346022.3	ENSP00000424372	P1	Q70EL2-1
USP45	ENST00000327681.10 linkuse as main transcript	c.2128G>A	p.Asp710Asn	missense_variant	16/18	1		ENSP00000333376	P1	Q70EL2-1
USP45	ENST00000496518.6 linkuse as main transcript	c.*1094G>A		3_prime_UTR_variant, NMD_transcript_variant	11/13	1		ENSP00000421248
USP45	ENST00000369233.6 linkuse as main transcript	c.1984G>A	p.Asp662Asn	missense_variant	15/17	5		ENSP00000358236

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.000724

AC:

180

AN:

248506

Hom.:

AF XY:

0.000722

AC XY:

AN XY:

134434

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.000355

Gnomad ASJ exome

AF:

0.00758

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000648

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.000531

AC:

773

AN:

1455008

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

408

AN XY:

723800

show subpopulations

Gnomad4 AFR exome

AF:

0.000420

Gnomad4 AMR exome

AF:

0.000408

Gnomad4 ASJ exome

AF:

0.00785

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000588

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000314

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152210

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000922

Hom.:

Bravo

AF:

0.000710

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000579

AC:

AN:

3470

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

Oct 21, 2021

The c.2128G>A (p.D710N) alteration is located in exon 16 (coding exon 15) of the USP45 gene. This alteration results from a G to A substitution at nucleotide position 2128, causing the aspartic acid (D) at amino acid position 710 to be replaced by an asparagine (N). 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

0.39

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.045

T;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.083

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.4

M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MVP

0.70

MPC

0.47

ClinPred

0.27

GERP RS

4.8

Varity_R

0.79

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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