3-124738240-G-T

Variant names:

• chr3-124738240-G-T
• rs1553748674
• NM_000373.4:c.982+1G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000373.4(UMPS):​c.982+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMPS NM_000373.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.85

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.46569645 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMPS	NM_000373.4	c.982+1G>T		splice_donor_variant, intron_variant	Intron 3 of 5	ENST00000232607.7	NP_000364.1
UMPS	XR_001740253.3	n.1003G>T		non_coding_transcript_exon_variant	Exon 3 of 4
UMPS	NR_033434.2	n.848+1G>T		splice_donor_variant, intron_variant	Intron 2 of 4
UMPS	NR_033437.2	n.1101+1G>T		splice_donor_variant, intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMPS	ENST00000232607.7	c.982+1G>T		splice_donor_variant, intron_variant	Intron 3 of 5	1	NM_000373.4	ENSP00000232607.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553748674; hg19: chr3-124457087;