Genetic Variant USP35:p.Pro32Leu (chr11-78196340-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020798.4(USP35):c.95C>T(p.Pro32Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,432,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

USP35
NM_020798.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3823868).

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.95C>T	p.Pro32Leu	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.95C>T	p.Pro32Leu	missense	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
USP35	ENST00000528910.5	TSL:1	c.-59-1596C>T		intron	N/A	ENSP00000436001.1	E9PRM2
USP35	ENST00000869542.1		c.95C>T	p.Pro32Leu	missense	Exon 2 of 11	ENSP00000539601.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000929

AC:

AN:

215218

AF XY:

0.00000838

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:

0.0000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1432224

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31706

American (AMR)

AF:

0.00

AC:

AN:

43388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

37718

South Asian (SAS)

AF:

0.00

AC:

AN:

85552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104846

Other (OTH)

AF:

0.00

AC:

AN:

59552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.00000839

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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

M_CAP

Benign

0.042

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

4.5

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.18

Sift

Benign

0.12

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.51

MutPred

0.41

Gain of helix (P = 0.0349)

MVP

0.44

MPC

1.0

ClinPred

0.90

GERP RS

4.3

Varity_R

0.22

gMVP

0.46

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over