13-48037831-G-T

Variant names:

• chr13-48037831-G-T
• rs762270086
• NM_018283.4:c.85G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018283.4(NUDT15):​c.85G>T​(p.Val29Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,447,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V29I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NUDT15 NM_018283.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 0 publications found

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]

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

LOC124903172 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT15	NM_018283.4	MANE Select	c.85G>T	p.Val29Phe	missense	Exon 1 of 3	NP_060753.1	Q9NV35
	NUDT15	NM_001304745.2		c.85G>T	p.Val29Phe	missense	Exon 1 of 2	NP_001291674.1
	NUDT15	NR_136687.2		n.106G>T		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT15	ENST00000258662.3	TSL:1 MANE Select	c.85G>T	p.Val29Phe	missense	Exon 1 of 3	ENSP00000258662.1	Q9NV35
	NUDT15	ENST00000875703.1		c.85G>T	p.Val29Phe	missense	Exon 1 of 4	ENSP00000545762.1
	NUDT15	ENST00000913136.1		c.85G>T	p.Val29Phe	missense	Exon 1 of 4	ENSP00000583195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447774 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 718754

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 41602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.00 AC: 0 AN: 83310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107436

Other (OTH) AF: 0.00 AC: 0 AN: 59940

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.88
MutPred		0.56		Gain of catalytic residue at K24 (P = 2e-04)
MVP		0.40
MPC		0.45
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.0040	Neutral
Varity_R		0.69
gMVP		0.81
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs762270086; hg19: chr13-48611967;