NM_018283.4:c.85G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018283.4(NUDT15):c.85G>C(p.Val29Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000625 in 1,599,306 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V29I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NUDT15
NM_018283.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.47

Publications

0 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:

SUCLA2 (HGNC:11448): (succinate-CoA ligase ADP-forming subunit beta) Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]

SUCLA2 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
Inheritance: AR, Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SUCLA2 links:

LOC124903172 (HGNC:):

LOC124903172 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018283.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NUDT15	NM_018283.4	MANE Select	c.85G>C	p.Val29Leu	missense	Exon 1 of 3	NP_060753.1	Q9NV35
NUDT15	NM_001304745.2		c.85G>C	p.Val29Leu	missense	Exon 1 of 2	NP_001291674.1
NUDT15	NR_136687.2		n.106G>C		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NUDT15	ENST00000258662.3	TSL:1 MANE Select	c.85G>C	p.Val29Leu	missense	Exon 1 of 3	ENSP00000258662.1	Q9NV35
NUDT15	ENST00000875703.1		c.85G>C	p.Val29Leu	missense	Exon 1 of 4	ENSP00000545762.1
NUDT15	ENST00000913136.1		c.85G>C	p.Val29Leu	missense	Exon 1 of 4	ENSP00000583195.1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000223

AC:

AN:

223836

AF XY:

0.00000829

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000243

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000996

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1447774

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718754

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

41602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25674

East Asian (EAS)

AF:

0.000153

AC:

AN:

39184

South Asian (SAS)

AF:

0.00

AC:

AN:

83310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4602

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107436

Other (OTH)

AF:

0.0000334

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41084

American (AMR)

AF:

0.00

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

Eigen

Benign

0.13

Eigen_PC

Benign

0.082

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

5.5

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.8

REVEL

Benign

0.24

Sift

Benign

0.059

Sift4G

Benign

0.075

Polyphen

0.89

Vest4

0.65

MutPred

0.56

Gain of catalytic residue at K24 (P = 2e-04)

MVP

0.27

MPC

0.41

ClinPred

0.58

GERP RS

3.9

PromoterAI

0.0032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.53

Mutation Taster

=261/39

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over