Genetic Variant NUDT15:p.Ala3Ala (chr13-48037755-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_018283.4(NUDT15):c.9C>A(p.Ala3Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NUDT15
NM_018283.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.303

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP7

Synonymous conserved (PhyloP=-0.303 with no splicing effect.

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.9C>A	p.Ala3Ala	synonymous	Exon 1 of 3	NP_060753.1	Q9NV35
NUDT15	NM_001304745.2		c.9C>A	p.Ala3Ala	synonymous	Exon 1 of 2	NP_001291674.1
NUDT15	NR_136687.2		n.30C>A		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.9C>A	p.Ala3Ala	synonymous	Exon 1 of 3	ENSP00000258662.1	Q9NV35
SUCLA2	ENST00000646804.1		c.-234G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000493977.1	A0A2R8YDQ9
SUCLA2	ENST00000643246.1		c.-312G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000496235.1	A0A2R8YF84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422616

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33112

American (AMR)

AF:

0.00

AC:

AN:

37224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25332

East Asian (EAS)

AF:

0.00

AC:

AN:

38462

South Asian (SAS)

AF:

0.00

AC:

AN:

81108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4260

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093568

Other (OTH)

AF:

0.0000170

AC:

AN:

58922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.7

(source)

DANN

Benign

0.73

PhyloP100

-0.30

PromoterAI

0.058

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over