dbSNP rs147390019: NUDT15:p.Arg139His (chr13-48045720-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_018283.4(NUDT15):c.416G>A(p.Arg139His) variant causes a missense change. The variant allele was found at a frequency of 0.00077 in 1,612,492 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 8 hom. )

Consequence

NUDT15
NM_018283.4 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 4.13

Publications

59 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006871134).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00222 (338/152226) while in subpopulation AMR AF = 0.0205 (313/15286). AF 95% confidence interval is 0.0186. There are 5 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 338 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT15	NM_018283.4 link	c.416G>A	p.Arg139His	missense_variant	Exon 3 of 3	ENST00000258662.3	NP_060753.1	Q9NV35
NUDT15	NR_136687.2 link	n.437G>A		non_coding_transcript_exon_variant	Exon 3 of 5
NUDT15	NR_136688.2 link	n.437G>A		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 link	c.416G>A	p.Arg139His	missense_variant	Exon 3 of 3	1	NM_018283.4	ENSP00000258662.1		Q9NV35

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00261

AC:

653

AN:

250140

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000619

AC:

904

AN:

1460266

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

407

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33382

American (AMR)

AF:

0.0173

AC:

770

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00139

AC:

AN:

39512

South Asian (SAS)

AF:

0.000128

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111264

Other (OTH)

AF:

0.000514

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00222

AC:

338

AN:

152226

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41544

American (AMR)

AF:

0.0205

AC:

313

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000654

Hom.:

Bravo

AF:

0.00291

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00182

AC:

221

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thiopurines, poor metabolism of, 2

Other:1

Oct 25, 2016

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

PhyloP100

4.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.38

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.34

MVP

0.47

MPC

0.38

ClinPred

0.041

GERP RS

5.4

Varity_R

0.35

gMVP

0.64

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over