rs3772809

Positions:

chr3-124743977-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

UMPS (HGNC:):

UMPS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 342935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-124743977-A-G is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
UMPS	NM_000373.4 linkuse as main transcript	c.1336A>G	p.Ile446Val	missense_variant	6/6	ENST00000232607.7	NP_000364.1	P11172-1A8K5J1
UMPS	NR_033434.2 linkuse as main transcript	n.1202A>G		non_coding_transcript_exon_variant	5/5
UMPS	NR_033437.2 linkuse as main transcript	n.1455A>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMPS	ENST00000232607.7 linkuse as main transcript	c.1336A>G	p.Ile446Val	missense_variant	6/6	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

GnomAD3 exomes

AF:

0.0225

AC:

5658

AN:

251478

Hom.:

120

AF XY:

0.0227

AC XY:

3087

AN XY:

135914

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 SAS exome

AF:

0.0432

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

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.0414

Gnomad4 ASJ exome

AF:

0.00804

Gnomad4 EAS exome

AF:

0.0616

Gnomad4 SAS exome

AF:

0.0408

Gnomad4 FIN exome

AF:

0.00713

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0133

AC:

2025

AN:

152354

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1046

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.0292

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.0557

Gnomad4 SAS

AF:

0.0456

Gnomad4 FIN

AF:

0.00631

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0138

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2019	- -

Oroticaciduria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

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

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

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

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

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