Genetic Variant NM_001346022.3:c.2090G>C (chr6-99439839-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001346022.3(USP45):c.2090G>C(p.Arg697Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R697H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USP45
NM_001346022.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.29

Publications

2 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

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.2090G>C	p.Arg697Pro	missense	Exon 16 of 18	NP_001332951.1	Q70EL2-1
USP45	NM_001080481.3		c.2090G>C	p.Arg697Pro	missense	Exon 16 of 18	NP_001073950.1	Q70EL2-1
USP45	NM_001346021.3		c.2090G>C	p.Arg697Pro	missense	Exon 16 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.2090G>C	p.Arg697Pro	missense	Exon 16 of 18	ENSP00000424372.1	Q70EL2-1
USP45	ENST00000327681.10	TSL:1	c.2090G>C	p.Arg697Pro	missense	Exon 16 of 18	ENSP00000333376.6	Q70EL2-1
USP45	ENST00000496518.6	TSL:1	n.*1056G>C		non_coding_transcript_exon	Exon 11 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

247214

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454526

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

43998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39274

South Asian (SAS)

AF:

0.00

AC:

AN:

84720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108346

Other (OTH)

AF:

0.00

AC:

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.8

PhyloP100

7.3

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.43

Sift

Benign

0.039

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.93

MutPred

0.67

Loss of MoRF binding (P = 0.0016)

MVP

0.76

MPC

0.57

ClinPred

1.0

GERP RS

4.8

Varity_R

0.82

gMVP

0.79

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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