rs3784619

Variant names:

• chr15-48333741-G-A
• rs3784619
• NM_001025248.2:c.420-676G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001025248.2(DUT):​c.420-676G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.798 in 152,166 control chromosomes in the GnomAD database, including 48,788 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48788 hom., cov: 31)
• Consequence: DUT NM_001025248.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• bone marrow failure and diabetes mellitus syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUT	NM_001025248.2	c.420-676G>A		intron_variant	Intron 2 of 6	ENST00000331200.8	NP_001020419.1
DUT	NM_001330286.2	c.165-676G>A		intron_variant	Intron 2 of 6		NP_001317215.1
DUT	NM_001948.4	c.156-676G>A		intron_variant	Intron 1 of 5		NP_001939.1
DUT	NM_001025249.1	c.87-676G>A		intron_variant	Intron 2 of 6		NP_001020420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUT	ENST00000331200.8	c.420-676G>A		intron_variant	Intron 2 of 6	1	NM_001025248.2	ENSP00000370376.2

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121404 AN: 152046 Hom.: 48767 Cov.: 31

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.792

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.798 AC: 121481 AN: 152166 Hom.: 48788 Cov.: 31 AF XY: 0.799 AC XY: 59446 AN XY: 74400

African (AFR) AF: 0.731 AC: 30328 AN: 41482

American (AMR) AF: 0.804 AC: 12292 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 2837 AN: 3464

East Asian (EAS) AF: 0.590 AC: 3043 AN: 5160

South Asian (SAS) AF: 0.784 AC: 3781 AN: 4824

European-Finnish (FIN) AF: 0.864 AC: 9167 AN: 10608

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57310 AN: 68020

Other (OTH) AF: 0.786 AC: 1661 AN: 2114

Alfa AF: 0.816 Hom.: 12463

Bravo AF: 0.791

Asia WGS AF: 0.674 AC: 2346 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.29
PhyloP100		0.075
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3784619; hg19: chr15-48625938;