Genetic Variant NUDT15:p.Gly15_Val18dup (chr13-48037782-A-AGGAGTCGGAGTC) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4PP3

The NM_018283.4(NUDT15):c.44_55dupGAGTCGGAGTCG(p.Gly15_Val18dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,042 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NUDT15
NM_018283.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 3 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT15	NM_018283.4 link	c.44_55dupGAGTCGGAGTCG	p.Gly15_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.44_55dupGAGTCGGAGTCG	p.Gly15_Val18dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_018283.4	ENSP00000258662.1	Q9NV35
SUCLA2	ENST00000646804.1 link	c.-273_-262dupGACTCCGACTCC		5_prime_UTR_variant	Exon 1 of 11			ENSP00000493977.1	A0A2R8YDQ9
SUCLA2	ENST00000643246.1 link	c.-351_-340dupGACTCCGACTCC		5_prime_UTR_variant	Exon 1 of 3			ENSP00000496235.1	A0A2R8YF84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000493

AC:

AN:

202908

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.0000258

AC:

AN:

38744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

38812

South Asian (SAS)

AF:

0.00

AC:

AN:

82228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101056

Other (OTH)

AF:

0.00

AC:

AN:

59458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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13-48037782-AGGAGTC-AGGAGTCGGAGTCGGAGTC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over