Genetic Variant ENST00000462091.5:n.-28A>G (chr3-124730405-T-G) – ACMG Classification: Likely_benign (-4 pts)

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0250

Publications

27 publications found

Variant links:

Genes affected

ENSG00000288713 (HGNC:):

ENSG00000288713 links:

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

UMPS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000462091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UMPS	NM_000373.4	MANE Select	c.-67T>G	upstream_gene	N/A	NP_000364.1	A8K5J1
UMPS	NR_033434.2		n.-47T>G	upstream_gene	N/A
UMPS	NR_033437.2		n.-47T>G	upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENSG00000288713	ENST00000683807.1		n.18A>C	non_coding_transcript_exon	Exon 1 of 3
UMPS	ENST00000232607.7	TSL:1 MANE Select	c.-67T>G	upstream_gene	N/A	ENSP00000232607.2	P11172-1
UMPS	ENST00000460034.5	TSL:1	n.-67T>G	upstream_gene	N/A	ENSP00000420409.1	F2Z303

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000444

AC:

107

AN:

240742

AF XY:

0.000404

show subpopulations

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:

AN:

1447676

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

719626

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33282

American (AMR)

AF:

0.0000225

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.0000775

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.000152

AC:

AN:

85326

European-Finnish (FIN)

AF:

0.000314

AC:

AN:

50882

Middle Eastern (MID)

AF:

0.000466

AC:

AN:

4296

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

1104268

Other (OTH)

AF:

0.0000167

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.336

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

3721

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.9

(source)

DANN

Benign

0.60

PhyloP100

0.025

PromoterAI

-0.12

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over