rs1426425595

Variant names:

• chr15-48331673-T-C
• rs1426425595
• NM_001025248.2:c.158T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001025248.2(DUT):​c.158T>C​(p.Ile53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUT NM_001025248.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84
• Publications: 0 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-AS1 (HGNC:55420): (DUT antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04791519).
• BP6: Variant 15-48331673-T-C is Benign according to our data. Variant chr15-48331673-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2245952.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025248.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUT	NM_001025248.2	MANE Select	c.158T>C	p.Ile53Thr	missense	Exon 1 of 7	NP_001020419.1	P33316-3
	DUT	NM_001330286.2		c.25+482T>C		intron	N/A	NP_001317215.1	H0YNW5
	DUT	NM_001025249.1		c.-54+194T>C		intron	N/A	NP_001020420.1	P33316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUT	ENST00000331200.8	TSL:1 MANE Select	c.158T>C	p.Ile53Thr	missense	Exon 1 of 7	ENSP00000370376.2	P33316-3
	DUT	ENST00000915906.1		c.158T>C	p.Ile53Thr	missense	Exon 1 of 7	ENSP00000585965.1
	DUT	ENST00000949573.1		c.158T>C	p.Ile53Thr	missense	Exon 1 of 6	ENSP00000619632.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382080 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 680762

African (AFR) AF: 0.00 AC: 0 AN: 29748

American (AMR) AF: 0.00 AC: 0 AN: 34780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24586

East Asian (EAS) AF: 0.00 AC: 0 AN: 34578

South Asian (SAS) AF: 0.00 AC: 0 AN: 77646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072476

Other (OTH) AF: 0.00 AC: 0 AN: 57196

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.7
DANN	Benign	0.22
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00076	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.024
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.27		Gain of sheet (P = 0.0036)
MVP		0.13
MPC		1.4
ClinPred		0.041	T
GERP RS		-4.6
PromoterAI		0.0084	Neutral
Varity_R		0.026
gMVP		0.059

Splicing

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

Other links and lift over

dbSNP: rs1426425595; hg19: chr15-48623870;