rs13146

Variant names:

• chr3-124743961-C-T
• rs13146
• NM_000373.4:c.1320C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000373.4(UMPS):​c.1320C>T​(p.Gly440Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,944 control chromosomes in the GnomAD database, including 27,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2592 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24834 hom.)
• Consequence: UMPS NM_000373.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.371
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-124743961-C-T is Benign according to our data. Variant chr3-124743961-C-T is described in ClinVar as Benign. ClinVar VariationId is 255958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.371 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.25 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.1320C>T	p.Gly440Gly	synonymous	Exon 6 of 6	NP_000364.1	A8K5J1
	UMPS	NR_033434.2		n.1186C>T		non_coding_transcript_exon	Exon 5 of 5
	UMPS	NR_033437.2		n.1439C>T		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMPS	ENST00000232607.7	TSL:1 MANE Select	c.1320C>T	p.Gly440Gly	synonymous	Exon 6 of 6	ENSP00000232607.2	P11172-1
	UMPS	ENST00000460034.5	TSL:1	n.*1064C>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000420409.1	F2Z303
	UMPS	ENST00000462091.5	TSL:1	n.*992C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000417893.1	F2Z3P2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27064 AN: 152068 Hom.: 2587 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.194 AC: 48885 AN: 251448 AF XY: 0.191

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.0998

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: 264732 AN: 1461758 Hom.: 24834 Cov.: 35 AF XY: 0.181 AC XY: 131672 AN XY: 727172

African (AFR) AF: 0.154 AC: 5146 AN: 33478

American (AMR) AF: 0.309 AC: 13839 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2677 AN: 26134

East Asian (EAS) AF: 0.214 AC: 8487 AN: 39686

South Asian (SAS) AF: 0.216 AC: 18617 AN: 86252

European-Finnish (FIN) AF: 0.191 AC: 10213 AN: 53412

Middle Eastern (MID) AF: 0.159 AC: 917 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194425 AN: 1111920

Other (OTH) AF: 0.172 AC: 10411 AN: 60384

GnomAD4 genome AF: 0.178 AC: 27090 AN: 152186 Hom.: 2592 Cov.: 33 AF XY: 0.181 AC XY: 13459 AN XY: 74394

African (AFR) AF: 0.159 AC: 6596 AN: 41540

American (AMR) AF: 0.256 AC: 3920 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 344 AN: 3468

East Asian (EAS) AF: 0.179 AC: 930 AN: 5182

South Asian (SAS) AF: 0.209 AC: 1007 AN: 4818

European-Finnish (FIN) AF: 0.201 AC: 2121 AN: 10572

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

European-Non Finnish (NFE) AF: 0.171 AC: 11607 AN: 67992

Other (OTH) AF: 0.175 AC: 370 AN: 2114

Alfa AF: 0.172 Hom.: 8155

Bravo AF: 0.180

Asia WGS AF: 0.192 AC: 668 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	not specified (2)
-	-	2	Oroticaciduria (2)
-	-	1	Hereditary orotic aciduria, type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.58
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs13146; hg19: chr3-124462808; COSMIC: COSV51736256; COSMIC: COSV51736256;