11-78196894-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_020798.4(USP35):​c.649C>T​(p.Leu217Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: USP35 NM_020798.4 synonymous
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.

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>T	p.Leu217Leu	synonymous	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>T	p.Leu217Leu	synonymous	Exon 2 of 11	ENSP00000431876.1	Q9P2H5-1
	USP35	ENST00000528910.5	TSL:1	c.-59-1042C>T		intron	N/A	ENSP00000436001.1	E9PRM2
	USP35	ENST00000530546.5	TSL:1	n.97C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000436253.1	H0YEP1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1319964 Hom.: 0 Cov.: 31 AF XY: 0.00000464 AC XY: 3 AN XY: 647054

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0000284 AC: 2 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: 9.55e-7 AC: 1 AN: 1047216

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00194278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.8
DANN	Benign	0.65
PhyloP100		2.2

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

Other links and lift over

dbSNP: rs1433294853; hg19: chr11-77907940;