Genetic Variant USP35:p.Arg59Cys (chr11-78196420-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020798.4(USP35):c.175C>T(p.Arg59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000371 in 1,294,522 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 0.00020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

USP35
NM_020798.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

Publications

0 publications found

Variant links:

Genes affected

USP35 (HGNC:20061): (ubiquitin specific peptidase 35) This gene encodes a member of the peptidase C19 family of ubiquitin-specific proteases. These deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin proteins from other proteins. The encoded protein associates with polarized mitochondria and has been shown to inhibit NF-kappa B activation and delay PARK2-mediated degradation of mitochondria. Expression of this gene is upregulated by the let-7a microRNA and reduced expression has been observed in human tumor tissues. [provided by RefSeq, Jul 2017]

USP35 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076602697).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020798.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP35	NM_020798.4	MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 2 of 11	NP_065849.1	Q9P2H5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP35	ENST00000529308.6	TSL:5 MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
USP35	ENST00000528910.5	TSL:1	c.-59-1516C>T		intron	N/A	ENSP00000436001.1	E9PRM2
USP35	ENST00000869542.1		c.175C>T	p.Arg59Cys	missense	Exon 2 of 11	ENSP00000539601.1

Frequencies

GnomAD3 genomes

AF:

0.000200

AC:

AN:

150042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000679

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000189

AC:

AN:

10588

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00379

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:

0.000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1144480

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

556672

show subpopulations

African (AFR)

AF:

0.000639

AC:

AN:

21908

American (AMR)

AF:

0.00

AC:

AN:

8386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14290

East Asian (EAS)

AF:

0.00

AC:

AN:

23454

South Asian (SAS)

AF:

0.00

AC:

AN:

44502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3154

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

957162

Other (OTH)

AF:

0.0000442

AC:

AN:

45276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.597

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

AF:

0.000200

AC:

AN:

150042

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

73234

show subpopulations

African (AFR)

AF:

0.000679

AC:

AN:

41230

American (AMR)

AF:

0.0000663

AC:

AN:

15072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67194

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.0000458

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.36

MutPred

0.29

Loss of disorder (P = 0.0676)

MVP

0.43

MPC

1.3

ClinPred

0.087

GERP RS

2.9

Varity_R

0.18

gMVP

0.27

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over