chr15-48342037-G-A

Position:

• chr15-48342037-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025248.2(DUT):​c.718G>A​(p.Glu240Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,579,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: DUT NM_001025248.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

Genes affected

DUT (HGNC:3078): (deoxyuridine triphosphatase) This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotetrameric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19. [provided by RefSeq, Jul 2008]

DUT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2203854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUT	NM_001025248.2	c.718G>A	p.Glu240Lys	missense_variant	7/7	ENST00000331200.8	NP_001020419.1
DUT	NM_001330286.2	c.463G>A	p.Glu155Lys	missense_variant	7/7		NP_001317215.1
DUT	NM_001948.4	c.454G>A	p.Glu152Lys	missense_variant	6/6		NP_001939.1
DUT	NM_001025249.1	c.385G>A	p.Glu129Lys	missense_variant	7/7		NP_001020420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUT	ENST00000331200.8	c.718G>A	p.Glu240Lys	missense_variant	7/7	1	NM_001025248.2	ENSP00000370376.2

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151358 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000489 AC: 11 AN: 225030 Hom.: 0 AF XY: 0.0000651 AC XY: 8 AN XY: 122798

Gnomad AFR exome AF: 0.000213

Gnomad AMR exome AF: 0.0000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000195

Gnomad SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.0000196 AC: 28 AN: 1427878 Hom.: 0 Cov.: 30 AF XY: 0.0000239 AC XY: 17 AN XY: 709852

Gnomad4 AFR exome AF: 0.0000649

Gnomad4 AMR exome AF: 0.0000262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0000500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000595 AC: 9 AN: 151358 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73830

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.718G>A (p.E240K) alteration is located in exon 7 (coding exon 7) of the DUT gene. This alteration results from a G to A substitution at nucleotide position 718, causing the glutamic acid (E) at amino acid position 240 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.080	T;T;T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D;T;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D;D;N;D
REVEL	Benign	0.11
Sift	Benign	0.62	T;T;T;T;T
Sift4G	Benign	0.72	T;T;T;T;T
Polyphen		0.017, 0.0010	.;.;B;.;B
Vest4		0.10
MVP		0.51
MPC		0.067
ClinPred		0.060	T
GERP RS		3.2
Varity_R		0.38
gMVP		0.62

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: rs371555609; hg19: chr15-48634234;