rs116855232

Positions:

• chr13-48045719-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000258662.3(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 (★★★). 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 ENST00000258662.3 missense
• Clinical Significance: drug response reviewed by expert panel B:1 O:3
• Conservation: PhyloP100: 4.41

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

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	c.415C>T	p.Arg139Cys	missense_variant	3/3	ENST00000258662.3	NP_060753.1
NUDT15	NR_136687.2	n.436C>T		non_coding_transcript_exon_variant	3/5
NUDT15	NR_136688.2	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	c.415C>T	p.Arg139Cys	missense_variant	3/3	1	NM_018283.4	ENSP00000258662	P1

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

GnomAD3 exomes AF: 0.0282 AC: 7054 AN: 249720 Hom.: 276 AF XY: 0.0281 AC XY: 3798 AN XY: 135108

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

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.: 67 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74362

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.: 64

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

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

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
MutationTaster	Benign	0.0046	P
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

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

Other links and lift over

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