chr13-48037782-A-AGGAGTC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM4PP3BP6BA1

The NM_018283.4(NUDT15):c.50_55dupGAGTCG(p.Gly17_Val18dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,587,328 control chromosomes in the GnomAD database, including 132 homozygotes. Variant has been reported in ClinVar as Likely benign,drug response (no stars).

Frequency

Genomes: 𝑓 0.0084 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 101 hom. )

Consequence

NUDT15
NM_018283.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign; drug response no assertion criteria provided B:1O:1

Conservation

PhyloP100: 8.38

Publications

30 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:

LOC124903172 (HGNC:):

LOC124903172 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: Mitochondrial, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

SUCLA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_018283.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 13-48037782-A-AGGAGTC is Benign according to our data. Variant chr13-48037782-A-AGGAGTC is described in ClinVar as Likely_benign|drug_response. ClinVar VariationId is 225204.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT15	NM_018283.4 link	c.50_55dupGAGTCG	p.Gly17_Val18dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000258662.3	NP_060753.1	Q9NV35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUDT15	ENST00000258662.3 link	c.50_55dupGAGTCG	p.Gly17_Val18dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_018283.4	ENSP00000258662.1	Q9NV35
SUCLA2	ENST00000646804.1 link	c.-267_-262dupGACTCC		5_prime_UTR_variant	Exon 1 of 11			ENSP00000493977.1	A0A2R8YDQ9
SUCLA2	ENST00000643246.1 link	c.-345_-340dupGACTCC		5_prime_UTR_variant	Exon 1 of 3			ENSP00000496235.1	A0A2R8YF84

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0583

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.0139

AC:

2829

AN:

202908

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.0495

Gnomad ASJ exome

AF:

0.000330

Gnomad EAS exome

AF:

0.0609

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00926

GnomAD4 exome

AF:

0.00559

AC:

8018

AN:

1435036

Hom.:

101

Cov.:

AF XY:

0.00518

AC XY:

3683

AN XY:

711128

show subpopulations

African (AFR)

AF:

0.00291

AC:

AN:

33322

American (AMR)

AF:

0.0490

AC:

1897

AN:

38742

Ashkenazi Jewish (ASJ)

AF:

0.000196

AC:

AN:

25502

East Asian (EAS)

AF:

0.0466

AC:

1809

AN:

38812

South Asian (SAS)

AF:

0.00173

AC:

142

AN:

82228

European-Finnish (FIN)

AF:

0.0129

AC:

667

AN:

51518

Middle Eastern (MID)

AF:

0.00250

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00276

AC:

3034

AN:

1101052

Other (OTH)

AF:

0.00599

AC:

356

AN:

59458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

491

981

1472

1962

2453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00837

AC:

1274

AN:

152292

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

675

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00255

AC:

106

AN:

41572

American (AMR)

AF:

0.0317

AC:

485

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0586

AC:

302

AN:

5154

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00332

AC:

226

AN:

68014

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.0106

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.4

Mutation Taster

=43/57

polymorphism (auto)

(source)

Splicing

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