3-124737895-G-C

Variant names:

• chr3-124737895-G-C
• rs1801019
• NM_000373.4:c.638G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000373.4(UMPS):​c.638G>C​(p.Gly213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,970 control chromosomes in the GnomAD database, including 27,370 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 0.18 (2589 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24781 hom.)
• Consequence: UMPS NM_000373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.92
• Publications: 69 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017309785).
• BP6: Variant 3-124737895-G-C is Benign according to our data. Variant chr3-124737895-G-C is described in ClinVar as Benign. ClinVar VariationId is 100127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	NM_000373.4	MANE Select	c.638G>C	p.Gly213Ala	missense	Exon 3 of 6	NP_000364.1
	UMPS	NR_033434.2		n.504G>C		non_coding_transcript_exon	Exon 2 of 5
	UMPS	NR_033437.2		n.757G>C		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	ENST00000232607.7	TSL:1 MANE Select	c.638G>C	p.Gly213Ala	missense	Exon 3 of 6	ENSP00000232607.2
	UMPS	ENST00000460034.5	TSL:1	n.*382G>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000420409.1
	UMPS	ENST00000462091.5	TSL:1	n.*310G>C		non_coding_transcript_exon	Exon 2 of 5	ENSP00000417893.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27042 AN: 152052 Hom.: 2584 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.194 AC: 48772 AN: 251114 AF XY: 0.191

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.181 AC: 264528 AN: 1461800 Hom.: 24781 Cov.: 33 AF XY: 0.181 AC XY: 131544 AN XY: 727198

African (AFR) AF: 0.154 AC: 5148 AN: 33480

American (AMR) AF: 0.309 AC: 13815 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2677 AN: 26136

East Asian (EAS) AF: 0.214 AC: 8497 AN: 39700

South Asian (SAS) AF: 0.215 AC: 18572 AN: 86258

European-Finnish (FIN) AF: 0.191 AC: 10210 AN: 53396

Middle Eastern (MID) AF: 0.158 AC: 911 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194294 AN: 1111976

Other (OTH) AF: 0.172 AC: 10404 AN: 60392

GnomAD4 genome AF: 0.178 AC: 27068 AN: 152170 Hom.: 2589 Cov.: 33 AF XY: 0.181 AC XY: 13451 AN XY: 74402

African (AFR) AF: 0.159 AC: 6599 AN: 41508

American (AMR) AF: 0.256 AC: 3909 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.179 AC: 928 AN: 5178

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4812

European-Finnish (FIN) AF: 0.201 AC: 2132 AN: 10602

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11588 AN: 67996

Other (OTH) AF: 0.174 AC: 369 AN: 2116

Alfa AF: 0.168 Hom.: 1647

Bravo AF: 0.180

TwinsUK AF: 0.179 AC: 662

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.155 AC: 681

ESP6500EA AF: 0.171 AC: 1470

ExAC AF: 0.189 AC: 22909

Asia WGS AF: 0.191 AC: 666 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.163

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oroticaciduria Benign:2

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.

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1 Other:1

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary orotic aciduria, type 1 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.13
Sift	Benign	0.46	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.23
ClinPred		0.026	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.57
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801019; hg19: chr3-124456742; COSMIC: COSV51739204; COSMIC: COSV51739204;