3-124730444-A-G

Variant names:

• chr3-124730444-A-G
• rs1139538
• ENST00000462091.5:n.-28A>G

Variant summary

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

The ENST00000462091.5(UMPS):​n.-28A>G variant causes a non coding transcript exon 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 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -1.35
• Publications: 21 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)

ENSG00000288713 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000462091.5. 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.-28A>G		upstream_gene	N/A	NP_000364.1
	UMPS	NR_033434.2		n.-8A>G		upstream_gene	N/A
	UMPS	NR_033437.2		n.-8A>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	ENST00000462091.5	TSL:1	n.-28A>G		non_coding_transcript_exon	Exon 1 of 5	ENSP00000417893.1
	UMPS	ENST00000462091.5	TSL:1	n.-28A>G		5_prime_UTR	Exon 1 of 5	ENSP00000417893.1
	UMPS	ENST00000232607.7	TSL:1 MANE Select	c.-28A>G		upstream_gene	N/A	ENSP00000232607.2

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

GnomAD2 exomes AF: 0.606 AC: 152139 AN: 251240 AF XY: 0.606

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 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

African (AFR) AF: 0.410 AC: 13704 AN: 33446

American (AMR) AF: 0.730 AC: 32630 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15874 AN: 26120

East Asian (EAS) AF: 0.633 AC: 25108 AN: 39666

South Asian (SAS) AF: 0.612 AC: 52744 AN: 86222

European-Finnish (FIN) AF: 0.528 AC: 28194 AN: 53352

Middle Eastern (MID) AF: 0.602 AC: 3296 AN: 5474

European-Non Finnish (NFE) AF: 0.586 AC: 651729 AN: 1111408

Other (OTH) AF: 0.586 AC: 35346 AN: 60316

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

African (AFR) AF: 0.420 AC: 17403 AN: 41484

American (AMR) AF: 0.670 AC: 10249 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2116 AN: 3472

East Asian (EAS) AF: 0.658 AC: 3391 AN: 5152

South Asian (SAS) AF: 0.621 AC: 2988 AN: 4810

European-Finnish (FIN) AF: 0.521 AC: 5498 AN: 10558

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 40040 AN: 67972

Other (OTH) AF: 0.589 AC: 1244 AN: 2112

Alfa AF: 0.583 Hom.: 18244

Bravo AF: 0.556

Asia WGS AF: 0.626 AC: 2179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Oroticaciduria Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-1.4
PromoterAI		0.10	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

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