13-48037782-AGGAGTC-A

Position:

• chr13-48037782-AGGAGTC-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM4 PP3 BP6_Moderate BS2

The NM_018283.4(NUDT15):​c.50_55delGAGTCG​(p.Gly17_Val18del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,587,330 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: NUDT15 NM_018283.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B: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 -3 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-AGGAGTC-A is Benign according to our data. Variant chr13-48037782-AGGAGTC-A is described in ClinVar as [Likely_benign]. Clinvar id is 2643811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT15	NM_018283.4	c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	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_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	1/3	1	NM_018283.4	ENSP00000258662.1
SUCLA2	ENST00000646804.1	c.-267_-262delGACTCC		5_prime_UTR_variant	1/11			ENSP00000493977.1
SUCLA2	ENST00000643246.1	c.-345_-340delGACTCC		5_prime_UTR_variant	1/3			ENSP00000496235.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00103 AC: 209 AN: 202908 Hom.: 0 AF XY: 0.000971 AC XY: 106 AN XY: 109212

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.000565

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.00172 AC: 2472 AN: 1435038 Hom.: 6 AF XY: 0.00173 AC XY: 1228 AN XY: 711128

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000387

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.000854

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74462

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.00137

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

Sep 01, 2023

NUDT15: PM4, BS1 -

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;