NM_020798.4:c.649C>A

Variant names:

• chr11-78196894-C-A
• rs1433294853
• NM_020798.4:c.649C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020798.4(USP35):​c.649C>A​(p.Leu217Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,319,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L217V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: USP35 NM_020798.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31755343).

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.649C>A	p.Leu217Met	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.649C>A	p.Leu217Met	missense	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
	USP35	ENST00000528910.5	TSL:1	c.-59-1042C>A		intron	N/A	ENSP00000436001.1	E9PRM2
	USP35	ENST00000530546.5	TSL:1	n.97C>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000436253.1	H0YEP1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000993 AC: 1 AN: 100710 AF XY: 0.00

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: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1319964 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 647054

African (AFR) AF: 0.00 AC: 0 AN: 27764

American (AMR) AF: 0.00 AC: 0 AN: 26974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20832

East Asian (EAS) AF: 0.00 AC: 0 AN: 33380

South Asian (SAS) AF: 0.00 AC: 0 AN: 70462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4902

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1047216

Other (OTH) AF: 0.00 AC: 0 AN: 54716

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.30		Gain of methylation at K215 (P = 0.0797)
MVP		0.69
MPC		0.98
ClinPred		0.31	T
GERP RS		2.8
Varity_R		0.22
gMVP		0.22
Mutation Taster		=82/18	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: rs1433294853; hg19: chr11-77907940;