rs138081800

Positions:

• chr22-24500105-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_016327.3(UPB1):​c.105-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000198 in 1,614,014 control chromosomes in the GnomAD database, including 2 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: UPB1 NM_016327.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 5.83

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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.7, offset of 4, new splice context is: tttcctgcccatctgggaAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 22-24500105-A-G is Pathogenic according to our data. Variant chr22-24500105-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-24500105-A-G is described in Lovd as [Pathogenic]. Variant chr22-24500105-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPB1	NM_016327.3	c.105-2A>G		splice_acceptor_variant, intron_variant		ENST00000326010.10	NP_057411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPB1	ENST00000326010.10	c.105-2A>G		splice_acceptor_variant, intron_variant		1	NM_016327.3	ENSP00000324343.5
UPB1	ENST00000382760.2	c.105-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000372208.2
UPB1	ENST00000415388.5	n.105-2021A>G		intron_variant		5		ENSP00000400684.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251290 Hom.: 1 AF XY: 0.000339 AC XY: 46 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461836 Hom.: 2 Cov.: 32 AF XY: 0.000215 AC XY: 156 AN XY: 727224

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of beta-ureidopropionase Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 24, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 09, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with beta-ureidopropionase deficiency (MIM#613161). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with pathogenic variants in UPB1 can range from severe neurological involvement with intellectual disability and seizures to normal neurological development (PMID: 35151535). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). Exon skipping has been suggested as an outcome; however, no data was provided (PMID: 17065070). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (315 heterozygotes, 2 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v4) at a frequency of [0.000002] (3 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This splice site variant has been reported more than ten times in ClinVar as pathogenic, and in multiple individuals in the literature with beta-ureidopropionase deficiency (PMIDs: 22525402, 17964839, 15385443). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2023	Variant summary: UPB1 c.105-2A>G is 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' splicing acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00038 in 251290 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.105-2A>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Deficiency Of Beta-Ureidopropionase (example, van Gennip_2000, van Kuilenburg_2004, Nakajima_2014, Righetti_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=9; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15385443, 11783491, 31980526, 32552793, 34426522, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	This sequence change affects an acceptor splice site in intron 1 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 (rs138081800, gnomAD 0.1%). Disruption of this splice site has been observed in individuals with ureidopropionase deficiency (PMID: 11783491, 15385443, 22525402, 24526388). ClinVar contains an entry for this variant (Variation ID: 4147). 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

Jan 13, 2022

The c.105-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 2 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 G allele has an overall frequency of 0.04% (100/282684) total alleles studied. The highest observed frequency was 0.13% (46/35436) of Latino alleles. This variant has been identified in the homozygous state in three individuals (two siblings) and confirmed in trans with a canonical splice variant in one individual with beta-ureidopropionase deficiency (van Kuilenburg, 2004; van Kuilenburg, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

UPB1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The UPB1 c.105-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is alternatively referred to as IVS1-2A>G in literature. It has been reported in the homozygous and compound heterozygous state in individuals with beta-ureidopropionase deficiency (van Gennip et al. 2000. PubMed ID: 11783491; van Kuilenburg et al. 2004. PubMed ID: 15385443). This variant was also reported in the homozygous in a father and daughter; however, it is unclear if the father is symptomatic (Table 1, Nakajima et al. 2014. PubMed ID: 24526388; van Kuilenburg et al. 2012. PubMed ID: 22525402). It is reported in 0.13%, including 1 homozygote, of alleles in individuals of Latino descent in gnomAD. This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751); however, the use of computer prediction programs is not equivalent to functional evidence. Taken together, while we suspect this variant could be pathogenic at this time interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.92		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138081800; hg19: chr22-24896073;