17-78803416-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001385174.1(USP36):c.2779G>A(p.Gly927Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP36 NM_001385174.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

USP36 (HGNC:20062): (ubiquitin specific peptidase 36) This gene encodes a member of the peptidase C19 or ubiquitin-specific protease family of cysteine proteases. Members of this family remove ubiquitin molecules from polyubiquitinated proteins. The encoded protein may deubiquitinate and stabilize the transcription factor c-Myc, also known as MYC, an important oncoprotein known to be upregulated in most human cancers. The encoded protease may also regulate the activation of autophagy. This gene exhibits elevated expression in some breast and lung cancers. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05803895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP36	NM_001385174.1	c.2779G>A	p.Gly927Ser	missense_variant	16/21	ENST00000449938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP36	ENST00000449938.7	c.2779G>A	p.Gly927Ser	missense_variant	16/21	1	NM_001385174.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 16, 2022

The c.2779G>A (p.G927S) alteration is located in exon 16 (coding exon 14) of the USP36 gene. This alteration results from a G to A substitution at nucleotide position 2779, causing the glycine (G) at amino acid position 927 to be replaced by a serine (S). 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	Benign	0.078
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	11
Dann	Benign	0.97
DEOGEN2	Benign	0.0065	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.065
Sift	Benign	0.085	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.15	B;B
Vest4		0.085
MutPred		0.28		Gain of phosphorylation at G927 (P = 0.0143);Gain of phosphorylation at G927 (P = 0.0143);
MVP		0.24
MPC		0.10
ClinPred		0.16	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.16

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-76799498;