3-124730559-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000373.4(UMPS):c.88A>G(p.Ser30Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,830 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (28 hom.)
• Consequence: UMPS NM_000373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011048943).
• BP6: Variant 3-124730559-A-G is Benign according to our data. Variant chr3-124730559-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255959.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr3-124730559-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00345 (525/152176) while in subpopulation AMR AF= 0.0248 (379/15284). AF 95% confidence interval is 0.0227. There are 10 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMPS	NM_000373.4	c.88A>G	p.Ser30Gly	missense_variant	1/6	ENST00000232607.7
UMPS	NR_033434.2	n.108A>G		non_coding_transcript_exon_variant	1/5
UMPS	NR_033437.2	n.108A>G		non_coding_transcript_exon_variant	1/7
UMPS	XR_001740253.3	n.108A>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMPS	ENST00000232607.7	c.88A>G	p.Ser30Gly	missense_variant	1/6	1	NM_000373.4	P1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152058 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00515 AC: 1295 AN: 251334 Hom.: 20 AF XY: 0.00398 AC XY: 541 AN XY: 135844

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00901

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00147 AC: 2152 AN: 1461654 Hom.: 28 Cov.: 32 AF XY: 0.00128 AC XY: 933 AN XY: 727078

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00519

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00865

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152176 Hom.: 10 Cov.: 32 AF XY: 0.00439 AC XY: 327 AN XY: 74416

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0100

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000465 Hom.: 0

Bravo AF: 0.00370

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00376 AC: 457

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Orotic aciduria Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary orotic aciduria, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.057	T;D
Polyphen		0.88	P;.
Vest4		0.69
MVP		0.88
MPC		1.1
ClinPred		0.11	T
GERP RS		5.2
Varity_R		0.82
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17843776; hg19: chr3-124449406;