Genetic Variant USP37:p.Glu826Lys (chr2-218463357-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_020935.3(USP37):c.2476G>A(p.Glu826Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

USP37
NM_020935.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.15

Variant links:

Genes affected

USP37 (HGNC:20063): (ubiquitin specific peptidase 37) Enables cysteine-type endopeptidase activity; protein kinase binding activity; and thiol-dependent deubiquitinase. Involved in G1/S transition of mitotic cell cycle; protein deubiquitination; and regulation of DNA replication. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

USP37 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39574087).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP37	NM_020935.3 link	c.2476G>A	p.Glu826Lys	missense_variant	Exon 22 of 26	ENST00000258399.8	NP_065986.3	Q86T82-1A0A024R416

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP37	ENST00000258399.8 link	c.2476G>A	p.Glu826Lys	missense_variant	Exon 22 of 26	1	NM_020935.3	ENSP00000258399.3	Q86T82-1
USP37	ENST00000418019.5 link	c.2476G>A	p.Glu826Lys	missense_variant	Exon 22 of 26	1		ENSP00000396585.1	Q86T82-1
USP37	ENST00000415516.5 link	c.2194G>A	p.Glu732Lys	missense_variant	Exon 20 of 24	1		ENSP00000400902.1	Q86T82-2
USP37	ENST00000454775.5 link	c.2476G>A	p.Glu826Lys	missense_variant	Exon 22 of 26	2		ENSP00000393662.1	Q86T82-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135892

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727212

show subpopulations

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:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2476G>A (p.E826K) alteration is located in exon 22 (coding exon 19) of the USP37 gene. This alteration results from a G to A substitution at nucleotide position 2476, causing the glutamic acid (E) at amino acid position 826 to be replaced by a lysine (K). 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.0091

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0040

T;T;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

.;.;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.8

L;L;.;L

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.26

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.53

MVP

0.16

MPC

0.44

ClinPred

0.95

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over