NM_000373.4:c.638G>C

Variant names:

• chr3-124737895-G-C
• rs1801019
• NM_000373.4:c.638G>C

Variant summary

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

The NM_000373.4(UMPS):​c.638G>C​(p.Gly213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,970 control chromosomes in the GnomAD database, including 27,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2589 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24781 hom.)
• Consequence: UMPS NM_000373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.92
• Publications: 69 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017309785).
• BP6: Variant 3-124737895-G-C is Benign according to our data. Variant chr3-124737895-G-C is described in ClinVar as Benign. ClinVar VariationId is 100127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 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.638G>C	p.Gly213Ala	missense	Exon 3 of 6	NP_000364.1	A8K5J1
	UMPS	NR_033434.2		n.504G>C		non_coding_transcript_exon	Exon 2 of 5
	UMPS	NR_033437.2		n.757G>C		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	ENST00000232607.7	TSL:1 MANE Select	c.638G>C	p.Gly213Ala	missense	Exon 3 of 6	ENSP00000232607.2	P11172-1
	UMPS	ENST00000460034.5	TSL:1	n.*382G>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000420409.1	F2Z303
	UMPS	ENST00000462091.5	TSL:1	n.*310G>C		non_coding_transcript_exon	Exon 2 of 5	ENSP00000417893.1	F2Z3P2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27042 AN: 152052 Hom.: 2584 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.194 AC: 48772 AN: 251114 AF XY: 0.191

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.181 AC: 264528 AN: 1461800 Hom.: 24781 Cov.: 33 AF XY: 0.181 AC XY: 131544 AN XY: 727198

African (AFR) AF: 0.154 AC: 5148 AN: 33480

American (AMR) AF: 0.309 AC: 13815 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2677 AN: 26136

East Asian (EAS) AF: 0.214 AC: 8497 AN: 39700

South Asian (SAS) AF: 0.215 AC: 18572 AN: 86258

European-Finnish (FIN) AF: 0.191 AC: 10210 AN: 53396

Middle Eastern (MID) AF: 0.158 AC: 911 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194294 AN: 1111976

Other (OTH) AF: 0.172 AC: 10404 AN: 60392

GnomAD4 genome AF: 0.178 AC: 27068 AN: 152170 Hom.: 2589 Cov.: 33 AF XY: 0.181 AC XY: 13451 AN XY: 74402

African (AFR) AF: 0.159 AC: 6599 AN: 41508

American (AMR) AF: 0.256 AC: 3909 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.179 AC: 928 AN: 5178

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4812

European-Finnish (FIN) AF: 0.201 AC: 2132 AN: 10602

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11588 AN: 67996

Other (OTH) AF: 0.174 AC: 369 AN: 2116

Alfa AF: 0.168 Hom.: 1647

Bravo AF: 0.180

TwinsUK AF: 0.179 AC: 662

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.155 AC: 681

ESP6500EA AF: 0.171 AC: 1470

ExAC AF: 0.189 AC: 22909

Asia WGS AF: 0.191 AC: 666 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.163

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.13
Sift	Benign	0.46	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.23
ClinPred		0.026	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.57
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801019; hg19: chr3-124456742; COSMIC: COSV51739204; COSMIC: COSV51739204;