rs143493067

Positions:

• chr22-24523618-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PP3_Strong PP5

The NM_016327.3(UPB1):​c.917-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,200 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: UPB1 NM_016327.3 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 B:1
• Conservation: PhyloP100: 9.74

Genes affected

UPB1 (HGNC:16297): (beta-ureidopropionase 1) This gene encodes a protein that belongs to the CN hydrolase family. Beta-ureidopropionase catalyzes the last step in the pyrimidine degradation pathway. The pyrimidine bases uracil and thymine are degraded via the consecutive action of dihydropyrimidine dehydrogenase (DHPDH), dihydropyrimidinase (DHP) and beta-ureidopropionase (UP) to beta-alanine and beta-aminoisobutyric acid, respectively. UP deficiencies are associated with N-carbamyl-beta-amino aciduria and may lead to abnormalities in neurological activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 8, new splice context is: gttcctttaaaactcaccAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-24523618-G-A is Pathogenic according to our data. Variant chr22-24523618-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445946.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=12, Likely_pathogenic=2, Benign=1}. Variant chr22-24523618-G-A is described in Lovd as [Pathogenic]. Variant chr22-24523618-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPB1	NM_016327.3	c.917-1G>A		splice_acceptor_variant		ENST00000326010.10
UPB1	XM_047441404.1	c.955-1G>A		splice_acceptor_variant
UPB1	XM_047441405.1	c.828-1G>A		splice_acceptor_variant
UPB1	XR_001755249.2	n.1011-1G>A		splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPB1	ENST00000326010.10	c.917-1G>A		splice_acceptor_variant		1	NM_016327.3	P1
UPB1	ENST00000498140.1	n.213-1G>A		splice_acceptor_variant, non_coding_transcript_variant		1
UPB1	ENST00000415388.5	c.*616-1G>A		splice_acceptor_variant, NMD_transcript_variant		5
UPB1	ENST00000486043.1	n.339-1G>A		splice_acceptor_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00178 AC: 447 AN: 251448 Hom.: 1 AF XY: 0.00183 AC XY: 249 AN XY: 135902

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00192 AC: 2808 AN: 1461862 Hom.: 6 Cov.: 32 AF XY: 0.00193 AC XY: 1407 AN XY: 727236

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74494

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00247 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00192 AC: 233

EpiCase AF: 0.00300

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of beta-ureidopropionase Pathogenic:8 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2021	Variant summary: UPB1 c.917-1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. Three predict the variant strengthens a cryptic exonic alternate 3' acceptor site. However, these predictions have yet to be unequivocally confirmed by functional studies. One publication reported a transcript with deletion of exon 6 presumably leading to a frameshift and probably a nonfunctional transcript. However, a transcript lacking exon 9 was not detected in this study (Kuilenburg_2006). Furthermore, the authors did not present primary data supporting their reported outcome. The variant allele was found at a frequency of 0.0018 in 251448 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in UPB1 causing Deficiency Of Beta-Ureidopropionase allowing no conclusion about variant significance. c.917-1G>A has been reported in the literature in individuals affected with Deficiency Of Beta-Ureidopropionase (example, Kuilenburg_2004, Kuilenburg_2012, Fang_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=3, Benign, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 07, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2022	The c.917-1G>A variant in UPB1 has been reported in a homozygote infant who suffered sudden unexplained death (Schon 2021 PMID: 33789662) and in at least 1 homozygous and 2 compound-heterozygous individuals affected with beta-ureidopropionase deficiency (Van Kuilenburg 2004 PMID: 15385443, Fang 2019 PMID: 30608453, Nakajima 2014 PMID: 24526388). In one of these individuals this variant was found in the compound heterozygous state with another loss-of-function variant affecting a canonical splice site that is classified as pathogenic by multiple submitters in ClinVar (Variation ID: 4147). The variant has been identified in 0.366% (38/10368) of Ashkenazi Jewish chromosomes and 0.277% (358/129172), including one homozygote, of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). These frequencies, however, are low enough to be consistent with a recessive carrier frequency for a disorder exhibiting low penetrance/variable expressivity as has been reported for beta-ureidopropionase deficiency (van Kuilenburg 2004 PMID: 15385443). This variant has also been reported in ClinVar (Variation ID 445946). It occurs in the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the UPB1 gene is an established disease mechanism in autosomal recessive beta-ureidopropionase deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive beta-ureidopropionase deficiency. ACMG/AMP Criteria applied: PVS1, PM3. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11783491, 15385443, 31589614, 30487145, 34426522, 33789662, 24526388, 30608453) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change affects an acceptor splice site in intron 8 of the UPB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in UPB1 are known to be pathogenic (PMID: 15385443, 22525402). This variant is present in population databases (rs143493067, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with beta-ureidopropionase deficiency (PMID: 11783491, 15385443, 24526388). This variant is also known as IVS8-1G>A. ClinVar contains an entry for this variant (Variation ID: 445946). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.917-1G>A intronic variant results from a G to A substitution one nucleotide before coding exon 9 of the UPB1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.18% (506/282852) total alleles studied. The highest observed frequency was 0.37% (38/10368) of Ashkenazi Jewish alleles. This mutation has been identified in the homozygous and compound heterozygous state in individuals with beta-ureidopropionase deficiency (van Kuilenburg, 2004; van Kuilenburg, 2012). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

UPB1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

The UPB1 c.917-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported previously in the compound heterozygous and homozygous state in multiple patients as causative for β-ureidopropionase deficiency (van Kuilenburg et al. 2004. PubMed ID: 15385443; van Kuilenburg et al. 2012. PubMed ID: 22525402; Fang et al. 2019. PubMed ID: 30608453; OMIM #613161). Specifically, the individual homozygous for this variant presented with a prolonged seizure event (status epilepticus) following a hospital visit for cyanosis (van Kuilenburg et al. 2004, PubMed ID: 15385443). This variant is reported in 0.37% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At PreventionGenetics, we have observed this variant in the homozygous state in an individual with biochemically confirmed β-ureidopropionase deficiency. Taken together, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 9
DS_AL_spliceai		1.0		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: rs143493067; hg19: chr22-24919586; COSMIC: COSV99065880;