Genetic Variant NUDT15:p.Val38Phe (chr13-48037858-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018283.4(NUDT15):c.112G>T(p.Val38Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. V38L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

NUDT15
NM_018283.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.28

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041145533).

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.112G>T	p.Val38Phe	missense	Exon 1 of 3	NP_060753.1	Q9NV35
NUDT15	NM_001304745.2		c.112G>T	p.Val38Phe	missense	Exon 1 of 2	NP_001291674.1
NUDT15	NR_136687.2		n.133G>T		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.112G>T	p.Val38Phe	missense	Exon 1 of 3	ENSP00000258662.1	Q9NV35
NUDT15	ENST00000875703.1		c.112G>T	p.Val38Phe	missense	Exon 1 of 4	ENSP00000545762.1
NUDT15	ENST00000913136.1		c.112G>T	p.Val38Phe	missense	Exon 1 of 4	ENSP00000583195.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.038

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.00060

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.78

M_CAP

Benign

0.0033

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

-1.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

REVEL

Benign

0.025

Sift

Benign

0.71

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.13

MutPred

0.48

Gain of catalytic residue at K35 (P = 0)

MVP

0.095

MPC

0.093

ClinPred

0.030

GERP RS

-1.3

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.19

gMVP

0.42

Mutation Taster

=81/19

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over