Genetic Variant USP45:p.Asn778Thr (chr6-99435828-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001346022.3(USP45):c.2333A>C(p.Asn778Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N778S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

USP45
NM_001346022.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.74

Publications

28 publications found

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:

PNISR-AS1 (HGNC:40958): (PNISR antisense RNA 1)

PNISR-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09839952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346022.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP45	NM_001346022.3	MANE Select	c.2333A>C	p.Asn778Thr	missense	Exon 18 of 18	NP_001332951.1	Q70EL2-1
USP45	NM_001080481.3		c.2333A>C	p.Asn778Thr	missense	Exon 18 of 18	NP_001073950.1	Q70EL2-1
USP45	NM_001346021.3		c.2333A>C	p.Asn778Thr	missense	Exon 18 of 18	NP_001332950.1	Q70EL2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP45	ENST00000500704.7	TSL:5 MANE Select	c.2333A>C	p.Asn778Thr	missense	Exon 18 of 18	ENSP00000424372.1	Q70EL2-1
USP45	ENST00000327681.10	TSL:1	c.2333A>C	p.Asn778Thr	missense	Exon 18 of 18	ENSP00000333376.6	Q70EL2-1
USP45	ENST00000496518.6	TSL:1	n.*1299A>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249602

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000587

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460336

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.0000675

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

85868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111368

Other (OTH)

AF:

0.00

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0012

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.064

M_CAP

Benign

0.0067

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

1.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

REVEL

Benign

0.054

Sift

Benign

0.63

Sift4G

Benign

0.49

Polyphen

0.0090

Vest4

0.051

MutPred

0.62

Loss of sheet (P = 0.1158)

MVP

0.40

MPC

0.089

ClinPred

0.056

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.12

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over