rs3772810

chr3-124744112-A-G

Variant summary

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

The NM_000373.4(UMPS):c.*28A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,612,548 control chromosomes in the GnomAD database, including 362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 32)
  • Exomes 𝑓: 0.016 (326 hom.)
• Consequence: UMPS NM_000373.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.108

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-124744112-A-G is Benign according to our data. Variant chr3-124744112-A-G is described in ClinVar as [Benign]. Clinvar id is 342937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-124744112-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMPS	NM_000373.4	c.*28A>G		3_prime_UTR_variant	6/6	ENST00000232607.7
UMPS	NR_033434.2	n.1337A>G		non_coding_transcript_exon_variant	5/5
UMPS	NR_033437.2	n.1590A>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMPS	ENST00000232607.7	c.*28A>G		3_prime_UTR_variant	6/6	1	NM_000373.4	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2053 AN: 151964 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.00633

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0226 AC: 5671 AN: 251170 Hom.: 119 AF XY: 0.0228 AC XY: 3094 AN XY: 135782

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.0409

Gnomad ASJ exome AF: 0.00864

Gnomad EAS exome AF: 0.0617

Gnomad SAS exome AF: 0.0432

Gnomad FIN exome AF: 0.00705

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0158 AC: 23007 AN: 1460466 Hom.: 326 Cov.: 32 AF XY: 0.0164 AC XY: 11881 AN XY: 726602

Gnomad4 AFR exome AF: 0.00260

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: 0.00715

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0136 AC: 2066 AN: 152082 Hom.: 36 Cov.: 32 AF XY: 0.0145 AC XY: 1077 AN XY: 74342

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0294

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.0461

Gnomad4 FIN AF: 0.00633

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0131 Hom.: 18

Bravo AF: 0.0140

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary orotic aciduria, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Orotic aciduria 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.3
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3772810; hg19: chr3-124462959; COSMIC: COSV51737949; COSMIC: COSV51737949;