chr11-78196720-C-A

Variant names:

• chr11-78196720-C-A
• NM_020798.4:c.475C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020798.4(USP35):​c.475C>A​(p.Pro159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P159S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP35 NM_020798.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.258
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0632143).

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.475C>A	p.Pro159Thr	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.475C>A	p.Pro159Thr	missense	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
	USP35	ENST00000528910.5	TSL:1	c.-59-1216C>A		intron	N/A	ENSP00000436001.1	E9PRM2
	USP35	ENST00000869542.1		c.475C>A	p.Pro159Thr	missense	Exon 2 of 11	ENSP00000539601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.26
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.34	N
REVEL	Benign	0.028
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.094	B
Vest4		0.14
MutPred		0.23		Loss of disorder (P = 0.0383)
MVP		0.29
MPC		1.1
ClinPred		0.043	T
GERP RS		1.1
Varity_R		0.049
gMVP		0.17
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr11-77907766;