chr13-48045719-C-T

Position:

chr13-48045719-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018283.4(NUDT15):c.415C>T(p.Arg139Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,612,064 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.013 ( 67 hom., cov: 32)

Exomes 𝑓: 0.012 ( 565 hom. )

Consequence

NUDT15
NM_018283.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:3

Conservation

PhyloP100: 4.41

Variant links:

Genes affected

NUDT15 (HGNC:23063): (nudix hydrolase 15) This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Apr 2016]

NUDT15 links:

NUDT15 (HGNC:):

NUDT15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037097335).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4 linkuse as main transcript	c.415C>T	p.Arg139Cys	missense_variant	3/3	ENST00000258662.3	NP_060753.1	Q9NV35
NUDT15	NR_136687.2 linkuse as main transcript	n.436C>T		non_coding_transcript_exon_variant	3/5
NUDT15	NR_136688.2 linkuse as main transcript	n.436C>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT15	ENST00000258662.3 linkuse as main transcript	c.415C>T	p.Arg139Cys	missense_variant	3/3	1	NM_018283.4	ENSP00000258662.1		Q9NV35

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1908

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0357

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.0712

Gnomad FIN

AF:

0.0217

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.0282

AC:

7054

AN:

249720

Hom.:

276

AF XY:

0.0281

AC XY:

3798

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.000994

Gnomad AMR exome

AF:

0.0600

Gnomad ASJ exome

AF:

0.00358

Gnomad EAS exome

AF:

0.105

Gnomad SAS exome

AF:

0.0666

Gnomad FIN exome

AF:

0.0232

Gnomad NFE exome

AF:

0.00348

Gnomad OTH exome

AF:

0.0219

GnomAD4 exome

AF:

0.0117

AC:

17014

AN:

1459930

Hom.:

565

Cov.:

AF XY:

0.0129

AC XY:

9382

AN XY:

726348

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.0563

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.104

Gnomad4 SAS exome

AF:

0.0644

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.00253

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0126

AC:

1912

AN:

152134

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1086

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.0357

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.0708

Gnomad4 FIN

AF:

0.0217

Gnomad4 NFE

AF:

0.00293

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00794

Hom.:

Bravo

AF:

0.0134

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.0278

AC:

3377

Asia WGS

AF:

0.0860

AC:

299

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

NUDT15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thiopurines, poor metabolism of, 2

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Oct 25, 2016

- -

azathioprine response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

mercaptopurine response - Dosage

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

REVEL

Benign

0.17

Sift

Benign

0.16

Sift4G

Benign

0.085

Polyphen

0.60

Vest4

0.095

MPC

0.11

ClinPred

0.015

GERP RS

4.5

Varity_R

0.39

gMVP

0.73

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