NM_001025248.2:c.557-394C>T

Variant names:

• chr15-48340895-C-T
• rs3784621
• NM_001025248.2:c.557-394C>T

Variant summary

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

The NM_001025248.2(DUT):​c.557-394C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 152,090 control chromosomes in the GnomAD database, including 37,800 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 0.68 (37800 hom., cov: 33)
• Consequence: DUT NM_001025248.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 14 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUT	NM_001025248.2	c.557-394C>T		intron_variant	Intron 4 of 6	ENST00000331200.8	NP_001020419.1
DUT	NM_001330286.2	c.302-394C>T		intron_variant	Intron 4 of 6		NP_001317215.1
DUT	NM_001948.4	c.293-394C>T		intron_variant	Intron 3 of 5		NP_001939.1
DUT	NM_001025249.1	c.224-394C>T		intron_variant	Intron 4 of 6		NP_001020420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUT	ENST00000331200.8	c.557-394C>T		intron_variant	Intron 4 of 6	1	NM_001025248.2	ENSP00000370376.2

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103600 AN: 151972 Hom.: 37809 Cov.: 33

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.691

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

GnomAD4 genome AF: 0.681 AC: 103613 AN: 152090 Hom.: 37800 Cov.: 33 AF XY: 0.681 AC XY: 50606 AN XY: 74364

African (AFR) AF: 0.424 AC: 17551 AN: 41432

American (AMR) AF: 0.686 AC: 10479 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2771 AN: 3468

East Asian (EAS) AF: 0.439 AC: 2272 AN: 5176

South Asian (SAS) AF: 0.640 AC: 3086 AN: 4822

European-Finnish (FIN) AF: 0.844 AC: 8938 AN: 10594

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56042 AN: 68014

Other (OTH) AF: 0.686 AC: 1445 AN: 2106

Alfa AF: 0.787 Hom.: 49090

Bravo AF: 0.660

Asia WGS AF: 0.509 AC: 1772 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.75
PhyloP100		0.15
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: rs3784621; hg19: chr15-48633092;