11-78200217-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020798.4(USP35):​c.1021C>T​(p.His341Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

USP35
NM_020798.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP35NM_020798.4 linkuse as main transcriptc.1021C>T p.His341Tyr missense_variant 5/11 ENST00000529308.6 NP_065849.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP35ENST00000529308.6 linkuse as main transcriptc.1021C>T p.His341Tyr missense_variant 5/115 NM_020798.4 ENSP00000431876 P1Q9P2H5-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249502
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135372
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsMar 20, 2023The c.1021C>T (p.H341Y) alteration is located in exon 5 (coding exon 4) of the USP35 gene. This alteration results from a C to T substitution at nucleotide position 1021, causing the histidine (H) at amino acid position 341 to be replaced by a tyrosine (Y). 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
Benign
0.27
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.015
.;T;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.025
D
MetaRNN
Uncertain
0.49
T;T;T
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.4
.;L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.22
Sift
Uncertain
0.010
D;D;D
Sift4G
Benign
0.099
T;D;D
Polyphen
1.0
.;D;.
Vest4
0.63, 0.74
MutPred
0.55
.;Loss of disorder (P = 0.1693);.;
MVP
0.70
MPC
0.095
ClinPred
0.84
D
GERP RS
4.7
Varity_R
0.21
gMVP
0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1320553288; hg19: chr11-77911263; API