Genetic Variant UPRT:p.Arg46Ser (chrX-75274392-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_145052.4(UPRT):c.138G>C(p.Arg46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,209,599 control chromosomes in the GnomAD database, including 1 homozygotes. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 1 hom. 4 hem. )

Consequence

UPRT
NM_145052.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0900

Variant links:

Genes affected

UPRT (HGNC:28334): (uracil phosphoribosyltransferase homolog) This gene encodes uracil phosphoribosyltransferase, which catalyzes the conversion of uracil and 5-phosphoribosyl-1-R-diphosphate to uridine monophosphate (UMP). This reaction is an important part of nucleotide metabolism, specifically the pyrimidine salvage pathway. The enzyme localizes to the nucleus and cytoplasm. The protein is a potential target for rational design of drugs to treat parasitic infections and cancer. [provided by RefSeq, Nov 2009]

UPRT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06085676).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPRT	NM_145052.4 link	c.138G>C	p.Arg46Ser	missense_variant	Exon 1 of 7	ENST00000373383.9	NP_659489.1	Q96BW1-1A8KAF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPRT	ENST00000373383.9 link	c.138G>C	p.Arg46Ser	missense_variant	Exon 1 of 7	1	NM_145052.4	ENSP00000362481.4		Q96BW1-1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111700

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

33866

show subpopulations

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

181163

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

65885

show subpopulations

Gnomad AFR exome

AF:

0.0000768

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1097899

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363271

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111700

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

33866

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.138G>C (p.R46S) alteration is located in exon 1 (coding exon 1) of the UPRT gene. This alteration results from a G to C substitution at nucleotide position 138, causing the arginine (R) at amino acid position 46 to be replaced by a serine (S). 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

0.097

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.5

DANN

Benign

0.82

DEOGEN2

Benign

0.15

T;.

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.31

N;N

REVEL

Benign

0.039

Sift

Benign

0.33

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0010

B;.

Vest4

0.12

MutPred

0.40

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

MVP

0.10

MPC

0.18

ClinPred

0.011

GERP RS

1.2

Varity_R

0.12

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over