NM_018283.4:c.50_55delGAGTCG

Variant names:

• chr13-48037782-AGGAGTC-A
• rs746071566
• NM_018283.4:c.50_55delGAGTCG

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 30 publications found

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]

SUCLA2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

  Inheritance: Mitochondrial, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

LOC124903172 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 2643811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 190 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018283.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT15	NM_018283.4	MANE Select	c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	Exon 1 of 3	NP_060753.1
	NUDT15	NM_001304745.2		c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	Exon 1 of 2	NP_001291674.1
	NUDT15	NR_136687.2		n.71_76delGAGTCG		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT15	ENST00000258662.3	TSL:1 MANE Select	c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000258662.1
	NUDT15	ENST00000875703.1		c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000545762.1
	NUDT15	ENST00000913136.1		c.50_55delGAGTCG	p.Gly17_Val18del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000583195.1

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

GnomAD2 exomes AF: 0.00103 AC: 209 AN: 202908 AF XY: 0.000971

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 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

African (AFR) AF: 0.000360 AC: 12 AN: 33322

American (AMR) AF: 0.000387 AC: 15 AN: 38744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25502

East Asian (EAS) AF: 0.0000515 AC: 2 AN: 38812

South Asian (SAS) AF: 0.000462 AC: 38 AN: 82228

European-Finnish (FIN) AF: 0.000854 AC: 44 AN: 51518

Middle Eastern (MID) AF: 0.000682 AC: 3 AN: 4402

European-Non Finnish (NFE) AF: 0.00208 AC: 2287 AN: 1101052

Other (OTH) AF: 0.00119 AC: 71 AN: 59458

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

African (AFR) AF: 0.000289 AC: 12 AN: 41572

American (AMR) AF: 0.00105 AC: 16 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68014

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.00137

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=49/151	disease causing

Splicing

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

Other links and lift over

dbSNP: rs746071566; hg19: chr13-48611918;