chr15-48342055-T-G

Position:

• chr15-48342055-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001025248.2(DUT):​c.736T>G​(p.Phe246Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUT NM_001025248.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUT	NM_001025248.2	c.736T>G	p.Phe246Val	missense_variant	7/7	ENST00000331200.8	NP_001020419.1
DUT	NM_001330286.2	c.481T>G	p.Phe161Val	missense_variant	7/7		NP_001317215.1
DUT	NM_001948.4	c.472T>G	p.Phe158Val	missense_variant	6/6		NP_001939.1
DUT	NM_001025249.1	c.403T>G	p.Phe135Val	missense_variant	7/7		NP_001020420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUT	ENST00000331200.8	c.736T>G	p.Phe246Val	missense_variant	7/7	1	NM_001025248.2	ENSP00000370376.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jul 14, 2021

The c.736T>G (p.F246V) alteration is located in exon 7 (coding exon 7) of the DUT gene. This alteration results from a T to G substitution at nucleotide position 736, causing the phenylalanine (F) at amino acid position 246 to be replaced by a valine (V). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.9	.;.;H;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.5	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;.;D;D
Vest4		0.86
MVP		0.90
MPC		0.42
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.77

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: rs1252151915; hg19: chr15-48634252;