11-78196420-C-G

Variant names:

• chr11-78196420-C-G
• rs764281675
• NM_020798.4:c.175C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020798.4(USP35):​c.175C>G​(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 1,144,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R59C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: USP35 NM_020798.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17832121).

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>G	p.Arg59Gly	missense	Exon 2 of 11	NP_065849.1	Q9P2H5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP35	ENST00000529308.6	TSL:5 MANE Select	c.175C>G	p.Arg59Gly	missense	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
	USP35	ENST00000528910.5	TSL:1	c.-59-1516C>G		intron	N/A	ENSP00000436001.1	E9PRM2
	USP35	ENST00000869542.1		c.175C>G	p.Arg59Gly	missense	Exon 2 of 11	ENSP00000539601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000175 AC: 2 AN: 1144480 Hom.: 0 Cov.: 30 AF XY: 0.00000180 AC XY: 1 AN XY: 556672

African (AFR) AF: 0.0000456 AC: 1 AN: 21908

American (AMR) AF: 0.00 AC: 0 AN: 8386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14290

East Asian (EAS) AF: 0.00 AC: 0 AN: 23454

South Asian (SAS) AF: 0.00 AC: 0 AN: 44502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3154

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 957162

Other (OTH) AF: 0.00 AC: 0 AN: 45276

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.25	B
Vest4		0.46
MutPred		0.33		Loss of stability (P = 0.0213)
MVP		0.38
MPC		1.3
ClinPred		0.14	T
GERP RS		2.9
Varity_R		0.17
gMVP		0.24
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs764281675; hg19: chr11-77907466;