rs1139538

chr3-124730444-A-Gchr3-124730444-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000462091.5(UMPS):c.-28A>G variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,612,770 control chromosomes in the GnomAD database, including 277,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23578 hom., cov: 32)
  • Exomes 𝑓: 0.59 (253971 hom.)
• Consequence: UMPS ENST00000462091.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.35

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-124730444-A-G is Benign according to our data. Variant chr3-124730444-A-G is described in ClinVar as [Benign]. Clinvar id is 100126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMPS	NM_000373.4			upstream_gene_variant		ENST00000232607.7
UMPS	NR_033434.2			upstream_gene_variant
UMPS	NR_033437.2			upstream_gene_variant
UMPS	XR_001740253.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMPS	ENST00000232607.7			upstream_gene_variant		1	NM_000373.4	P1
	ENST00000683807.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83484 AN: 151940 Hom.: 23564 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.589

GnomAD3 exomes AF: 0.606 AC: 152139 AN: 251240 Hom.: 46846 AF XY: 0.606 AC XY: 82289 AN XY: 135828

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.682

Gnomad SAS exome AF: 0.618

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.588 AC: 858625 AN: 1460710 Hom.: 253971 Cov.: 51 AF XY: 0.589 AC XY: 427604 AN XY: 726566

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.730

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.549 AC: 83539 AN: 152060 Hom.: 23578 Cov.: 32 AF XY: 0.552 AC XY: 41034 AN XY: 74334

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.589

Gnomad4 OTH AF: 0.589

Alfa AF: 0.585 Hom.: 12618

Bravo AF: 0.556

Asia WGS AF: 0.626 AC: 2179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orotic aciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.13
Dann	Benign	0.38

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

Other links and lift over

dbSNP: rs1139538; hg19: chr3-124449291; COSMIC: COSV51739227; COSMIC: COSV51739227;