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rs928740792

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000373.4(UMPS):c.1375C>G(p.Arg459Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

UMPS
NM_000373.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37
Variant links:
Genes affected
UMPS (HGNC:12563): (uridine monophosphate synthetase) This gene encodes a uridine 5'-monophosphate synthase. The encoded protein is a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway. The first reaction is carried out by the N-terminal enzyme orotate phosphoribosyltransferase which converts orotic acid to orotidine-5'-monophosphate. The terminal reaction is carried out by the C-terminal enzyme OMP decarboxylase which converts orotidine-5'-monophosphate to uridine monophosphate. Defects in this gene are the cause of hereditary orotic aciduria. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UMPSNM_000373.4 linkuse as main transcriptc.1375C>G p.Arg459Gly missense_variant 6/6 ENST00000232607.7
UMPSNR_033434.2 linkuse as main transcriptn.1241C>G non_coding_transcript_exon_variant 5/5
UMPSNR_033437.2 linkuse as main transcriptn.1494C>G non_coding_transcript_exon_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UMPSENST00000232607.7 linkuse as main transcriptc.1375C>G p.Arg459Gly missense_variant 6/61 NM_000373.4 P1P11172-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461860
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74340
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary orotic aciduria, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 11, 2022This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 459 of the UMPS protein (p.Arg459Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UMPS-related conditions. ClinVar contains an entry for this variant (Variation ID: 529221). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.053
T
BayesDel_noAF
Benign
-0.31
Cadd
Benign
16
Dann
Benign
0.97
DEOGEN2
Benign
0.35
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.92
D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.25
Sift
Benign
0.060
T
Sift4G
Benign
0.16
T
Polyphen
0.0010
B
Vest4
0.41
MutPred
0.62
Loss of MoRF binding (P = 0.0519);
MVP
0.77
MPC
0.26
ClinPred
0.26
T
GERP RS
2.9
Varity_R
0.78
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs928740792; hg19: chr3-124462863; API