13-48037869-C-A

Position:

• chr13-48037869-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_018283.4(NUDT15):​c.123C>A​(p.Gly41Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,607,074 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (15 hom.)
• Consequence: NUDT15 NM_018283.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0200

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 13-48037869-C-A is Benign according to our data. Variant chr13-48037869-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041752.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.
• BS2: High AC in GnomAd4 at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.123C>A	p.Gly41Gly	synonymous_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.123C>A	p.Gly41Gly	synonymous_variant	1/3	1	NM_018283.4	ENSP00000258662.1
SUCLA2	ENST00000646804.1	c.-348G>T		5_prime_UTR_variant	1/11			ENSP00000493977.1
SUCLA2	ENST00000643246.1	c.-426G>T		5_prime_UTR_variant	1/3			ENSP00000496235.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00194 AC: 458 AN: 235958 Hom.: 6 AF XY: 0.00218 AC XY: 278 AN XY: 127478

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000624

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.00458

Gnomad FIN exome AF: 0.000246

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00174 AC: 2527 AN: 1454738 Hom.: 15 Cov.: 31 AF XY: 0.00186 AC XY: 1346 AN XY: 722910

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.000659

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00448

Gnomad4 FIN exome AF: 0.000377

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74494

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00131

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

NUDT15: BP4, BS2 -

NUDT15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.7
DANN	Benign	0.95

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: rs138959770; hg19: chr13-48612005;