chr13-48037782-A-AGGAGTC

Position:

• chr13-48037782-A-AGGAGTC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM4 PP3 BP6 BA1

The NM_018283.4(NUDT15):​c.50_55dupGAGTCG​(p.Gly17_Val18dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,587,328 control chromosomes in the GnomAD database, including 132 homozygotes. Variant has been reported in ClinVar as Likely benign,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.0084 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (101 hom.)
• Consequence: NUDT15 NM_018283.4 disruptive_inframe_insertion
• 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 Likely_benign. Variant got -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_018283.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 13-48037782-A-AGGAGTC is Benign according to our data. Variant chr13-48037782-A-AGGAGTC is described in ClinVar as [Likely_benign, drug_response]. Clinvar id is 225204.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.50_55dupGAGTCG	p.Gly17_Val18dup	disruptive_inframe_insertion	1/3	ENST00000258662.3	NP_060753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT15	ENST00000258662.3	c.50_55dupGAGTCG	p.Gly17_Val18dup	disruptive_inframe_insertion	1/3	1	NM_018283.4	ENSP00000258662.1
SUCLA2	ENST00000646804.1	c.-267_-262dupGACTCC		5_prime_UTR_variant	1/11			ENSP00000493977.1
SUCLA2	ENST00000643246.1	c.-345_-340dupGACTCC		5_prime_UTR_variant	1/3			ENSP00000496235.1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152174 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0583

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0139 AC: 2829 AN: 202908 Hom.: 73 AF XY: 0.0116 AC XY: 1271 AN XY: 109212

Gnomad AFR exome AF: 0.00158

Gnomad AMR exome AF: 0.0495

Gnomad ASJ exome AF: 0.000330

Gnomad EAS exome AF: 0.0609

Gnomad SAS exome AF: 0.00153

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00926

GnomAD4 exome AF: 0.00559 AC: 8018 AN: 1435036 Hom.: 101 Cov.: 31 AF XY: 0.00518 AC XY: 3683 AN XY: 711128

Gnomad4 AFR exome AF: 0.00291

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.000196

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00276

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.00837 AC: 1274 AN: 152292 Hom.: 31 Cov.: 33 AF XY: 0.00907 AC XY: 675 AN XY: 74462

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0317

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0586

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00709

Bravo AF: 0.0106

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

Jul 22, 2021

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746071566; hg19: chr13-48611918;