NM_018283.4:c.415C>T

Variant names:

• chr13-48045719-C-T
• rs116855232
• NM_018283.4:c.415C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (67 hom., cov: 32)
  • Exomes 𝑓: 0.012 (565 hom.)
• Consequence: NUDT15 NM_018283.4 missense
• Clinical Significance: drug response reviewed by expert panel B:1 O:3
• Conservation: PhyloP100: 4.41
• Publications: 299 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.415C>T	p.Arg139Cys	missense_variant	Exon 3 of 3	ENST00000258662.3	NP_060753.1
NUDT15	NR_136687.2	n.436C>T		non_coding_transcript_exon_variant	Exon 3 of 5
NUDT15	NR_136688.2	n.436C>T		non_coding_transcript_exon_variant	Exon 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT15	ENST00000258662.3	c.415C>T	p.Arg139Cys	missense_variant	Exon 3 of 3	1	NM_018283.4	ENSP00000258662.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1908 AN: 152016 Hom.: 66 Cov.: 32

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

GnomAD2 exomes AF: 0.0282 AC: 7054 AN: 249720 AF XY: 0.0281

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 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.: 30 AF XY: 0.0129 AC XY: 9382 AN XY: 726348

African (AFR) AF: 0.00132 AC: 44 AN: 33358

American (AMR) AF: 0.0563 AC: 2495 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26106

East Asian (EAS) AF: 0.104 AC: 4078 AN: 39390

South Asian (SAS) AF: 0.0644 AC: 5532 AN: 85900

European-Finnish (FIN) AF: 0.0206 AC: 1102 AN: 53382

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5766

European-Non Finnish (NFE) AF: 0.00253 AC: 2809 AN: 1111424

Other (OTH) AF: 0.0133 AC: 805 AN: 60312

GnomAD4 genome AF: 0.0126 AC: 1912 AN: 152134 Hom.: 67 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74362

African (AFR) AF: 0.000915 AC: 38 AN: 41516

American (AMR) AF: 0.0357 AC: 546 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.101 AC: 525 AN: 5182

South Asian (SAS) AF: 0.0708 AC: 341 AN: 4816

European-Finnish (FIN) AF: 0.0217 AC: 229 AN: 10564

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00293 AC: 199 AN: 67994

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00852 Hom.: 104

Bravo AF: 0.0134

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.0278 AC: 3377

Asia WGS AF: 0.0860 AC: 299 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

NUDT15-related disorder Benign:1

Jul 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 25, 2016

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

azathioprine response - Toxicity Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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: Dosage

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.16	T
Sift4G	Benign	0.085	T
Polyphen		0.60	P
Vest4		0.095
MPC		0.11
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.39
gMVP		0.73
Mutation Taster		=87/13	polymorphism (auto)

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: rs116855232; hg19: chr13-48619855; COSMIC: COSV51642279; COSMIC: COSV51642279;