ENST00000462091.5:n.-28A>G

Variant names:

• chr3-124730405-T-G
• rs2279199
• ENST00000683807.1:n.18A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000462091.5(UMPS):​n.-67T>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,447,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: UMPS ENST00000462091.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 27 publications found

Genes affected

ENSG00000288713 (HGNC:):

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMPS	NM_000373.4	c.-67T>G		upstream_gene_variant		ENST00000232607.7	NP_000364.1
UMPS	NR_033434.2	n.-47T>G		upstream_gene_variant
UMPS	NR_033437.2	n.-47T>G		upstream_gene_variant
UMPS	XR_001740253.3	n.-47T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMPS	ENST00000232607.7	c.-67T>G		upstream_gene_variant		1	NM_000373.4	ENSP00000232607.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000444 AC: 107 AN: 240742 AF XY: 0.000404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.0000387 AC: 56 AN: 1447676 Hom.: 0 Cov.: 29 AF XY: 0.0000403 AC XY: 29 AN XY: 719626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.0000225 AC: 1 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.0000775 AC: 2 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85326

European-Finnish (FIN) AF: 0.000314 AC: 16 AN: 50882

Middle Eastern (MID) AF: 0.000466 AC: 2 AN: 4296

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1104268

Other (OTH) AF: 0.0000167 AC: 1 AN: 59806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 3721

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.60
PhyloP100		0.025
PromoterAI		-0.12	Neutral

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: rs2279199; hg19: chr3-124449252;