rs3772809

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000373.4(UMPS):c.1336A>G(p.Ile446Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,614,206 control chromosomes in the GnomAD database, including 362 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 32)

Exomes 𝑓: 0.016 ( 327 hom. )

Consequence

UMPS
NM_000373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.969

Publications

19 publications found

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]

UMPS Gene-Disease associations (from GenCC):

orotic aciduria
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

UMPS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025242865).

BP6

Variant 3-124743977-A-G is Benign according to our data. Variant chr3-124743977-A-G is described in ClinVar as Benign. ClinVar VariationId is 342935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMPS	NM_000373.4 link	c.1336A>G	p.Ile446Val	missense_variant	Exon 6 of 6	ENST00000232607.7	NP_000364.1	P11172-1A8K5J1
UMPS	NR_033434.2 link	n.1202A>G		non_coding_transcript_exon_variant	Exon 5 of 5
UMPS	NR_033437.2 link	n.1455A>G		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMPS	ENST00000232607.7 link	c.1336A>G	p.Ile446Val	missense_variant	Exon 6 of 6	1	NM_000373.4	ENSP00000232607.2		P11172-1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2014

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0287

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.0454

Gnomad FIN

AF:

0.00631

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0225

AC:

5658

AN:

251478

AF XY:

0.0227

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0409

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.0617

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0157

AC:

22978

AN:

1461852

Hom.:

327

Cov.:

AF XY:

0.0163

AC XY:

11871

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.0414

AC:

1852

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00804

AC:

210

AN:

26132

East Asian (EAS)

AF:

0.0616

AC:

2447

AN:

39692

South Asian (SAS)

AF:

0.0408

AC:

3520

AN:

86258

European-Finnish (FIN)

AF:

0.00713

AC:

381

AN:

53418

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0122

AC:

13524

AN:

1111986

Other (OTH)

AF:

0.0160

AC:

967

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1332

2665

3997

5330

6662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0133

AC:

2025

AN:

152354

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1046

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41588

American (AMR)

AF:

0.0292

AC:

447

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.0557

AC:

289

AN:

5184

South Asian (SAS)

AF:

0.0456

AC:

220

AN:

4822

European-Finnish (FIN)

AF:

0.00631

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

820

AN:

68036

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

111

223

334

446

557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.0216

AC:

2621

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oroticaciduria

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary orotic aciduria, type 1

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.19

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.030

PhyloP100

0.97

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.22

REVEL

Benign

0.036

Sift

Benign

0.55

Sift4G

Benign

0.88

Polyphen

0.0

Vest4

0.039

MPC

0.17

ClinPred

0.0031

GERP RS

2.8

Varity_R

0.067

gMVP

0.43

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over