chr11-78200231-C-G

Position:

• chr11-78200231-C-G

Variant summary

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

The NM_020798.4(USP35):​c.1035C>G​(p.His345Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USP35 NM_020798.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

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
USP35	NM_020798.4	c.1035C>G	p.His345Gln	missense_variant	5/11	ENST00000529308.6	NP_065849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP35	ENST00000529308.6	c.1035C>G	p.His345Gln	missense_variant	5/11	5	NM_020798.4	ENSP00000431876	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.1035C>G (p.H345Q) alteration is located in exon 5 (coding exon 4) of the USP35 gene. This alteration results from a C to G substitution at nucleotide position 1035, causing the histidine (H) at amino acid position 345 to be replaced by a glutamine (Q). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.078	.;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.82, 0.81
MutPred		0.53		.;Gain of sheet (P = 0.0016);.;
MVP		0.52
MPC		0.082
ClinPred		0.93	D
GERP RS		1.9
Varity_R		0.80
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-77911277;