chr13-48037782-A-C

Position:

• chr13-48037782-A-C

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.36A>C​(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,587,332 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (9 hom.)
• Consequence: NUDT15 NM_018283.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.64

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=-1.2).
• BP6: Variant 13-48037782-A-C is Benign according to our data. Variant chr13-48037782-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3234192.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.64 with no splicing effect.
• BS2: High AC in GnomAd4 at 295 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.36A>C	p.Pro12Pro	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.36A>C	p.Pro12Pro	synonymous_variant	1/3	1	NM_018283.4	ENSP00000258662.1
SUCLA2	ENST00000646804.1	c.-261T>G		5_prime_UTR_variant	1/11			ENSP00000493977.1
SUCLA2	ENST00000643246.1	c.-339T>G		5_prime_UTR_variant	1/3			ENSP00000496235.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152174 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00151 AC: 306 AN: 202908 Hom.: 0 AF XY: 0.00154 AC XY: 168 AN XY: 109212

Gnomad AFR exome AF: 0.0000789

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000765

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00157 AC: 2258 AN: 1435040 Hom.: 9 Cov.: 31 AF XY: 0.00161 AC XY: 1148 AN XY: 711130

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000129

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000158

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00182

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152292 Hom.: 4 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74462

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00314 Hom.: 3

Bravo AF: 0.00153

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

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, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.57
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61746486; hg19: chr13-48611918;