chr13-48037798-G-A

Position:

• chr13-48037798-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018283.4(NUDT15):​c.52G>A​(p.Val18Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,593,114 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: NUDT15 NM_018283.4 missense
• Clinical Significance: Likely benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 8.38

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]

NUDT15 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009341568).
• BP6: Variant 13-48037798-G-A is Benign according to our data. Variant chr13-48037798-G-A is described in ClinVar as [Likely_benign, drug_response]. Clinvar id is 225203.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.52G>A	p.Val18Ile	missense_variant	1/3	ENST00000258662.3	NP_060753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT15	ENST00000258662.3	c.52G>A	p.Val18Ile	missense_variant	1/3	1	NM_018283.4	ENSP00000258662.1
SUCLA2	ENST00000646804.1	c.-277C>T		5_prime_UTR_variant	1/11			ENSP00000493977.1
SUCLA2	ENST00000643246.1	c.-355C>T		5_prime_UTR_variant	1/3			ENSP00000496235.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000912 AC: 193 AN: 211708 Hom.: 3 AF XY: 0.000886 AC XY: 101 AN XY: 113942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0112

Gnomad SAS exome AF: 0.000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.000374

GnomAD4 exome AF: 0.000366 AC: 527 AN: 1440760 Hom.: 4 Cov.: 31 AF XY: 0.000375 AC XY: 268 AN XY: 714488

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000235

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.000754

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000589

ExAC AF: 0.000840 AC: 101

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

NUDT15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

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

drug response, no assertion criteria provided

literature only

OMIM

Oct 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0059	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.27
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.42
MVP		0.21
MPC		0.38
ClinPred		0.12	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs186364861; hg19: chr13-48611934;