rs2291078

Variant names:

• chr3-124740091-T-A
• rs2291078
• NM_000373.4:c.1050T>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000373.4(UMPS):​c.1050T>A​(p.Val350Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,088 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (37 hom., cov: 32)
  • Exomes 𝑓: 0.017 (452 hom.)
• Consequence: UMPS NM_000373.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.736
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-124740091-T-A is Benign according to our data. Variant chr3-124740091-T-A is described in ClinVar as Benign. ClinVar VariationId is 100129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.736 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0572 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	NM_000373.4	MANE Select	c.1050T>A	p.Val350Val	synonymous	Exon 4 of 6	NP_000364.1
	UMPS	NR_033434.2		n.916T>A		non_coding_transcript_exon	Exon 3 of 5
	UMPS	NR_033437.2		n.1169T>A		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	ENST00000232607.7	TSL:1 MANE Select	c.1050T>A	p.Val350Val	synonymous	Exon 4 of 6	ENSP00000232607.2
	UMPS	ENST00000460034.5	TSL:1	n.*794T>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000420409.1
	UMPS	ENST00000462091.5	TSL:1	n.*722T>A		non_coding_transcript_exon	Exon 3 of 5	ENSP00000417893.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2124 AN: 152094 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0245 AC: 6149 AN: 251454 AF XY: 0.0253

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.0691

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0169 AC: 24727 AN: 1461876 Hom.: 452 Cov.: 32 AF XY: 0.0178 AC XY: 12954 AN XY: 727242

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.0420 AC: 1880 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00803 AC: 210 AN: 26136

East Asian (EAS) AF: 0.0780 AC: 3098 AN: 39700

South Asian (SAS) AF: 0.0517 AC: 4459 AN: 86256

European-Finnish (FIN) AF: 0.00713 AC: 381 AN: 53420

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5762

European-Non Finnish (NFE) AF: 0.0122 AC: 13555 AN: 1112002

Other (OTH) AF: 0.0172 AC: 1039 AN: 60396

GnomAD4 genome AF: 0.0140 AC: 2135 AN: 152212 Hom.: 37 Cov.: 32 AF XY: 0.0150 AC XY: 1119 AN XY: 74396

African (AFR) AF: 0.00356 AC: 148 AN: 41536

American (AMR) AF: 0.0296 AC: 453 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.0629 AC: 326 AN: 5186

South Asian (SAS) AF: 0.0530 AC: 255 AN: 4810

European-Finnish (FIN) AF: 0.00623 AC: 66 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 822 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0115 Hom.: 6

Bravo AF: 0.0142

Asia WGS AF: 0.0490 AC: 169 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0108

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary orotic aciduria, type 1 (1)
-	-	1	not provided (2)
-	-	1	Oroticaciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.7
DANN	Benign	0.73
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2291078; hg19: chr3-124458938; COSMIC: COSV51737943; COSMIC: COSV51737943;