rs118163237

chr22-24523679-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_016327.3(UPB1):c.977G>A(p.Arg326Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,614,252 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R326R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00095 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (11 hom.)
• Consequence: UPB1 NM_016327.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010152787).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000952 (145/152370) while in subpopulation EAS AF= 0.0254 (132/5188). AF 95% confidence interval is 0.0219. There are 4 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPB1	NM_016327.3	c.977G>A	p.Arg326Gln	missense_variant	9/10	ENST00000326010.10
UPB1	XM_047441404.1	c.1015G>A	p.Gly339Arg	missense_variant	10/10
UPB1	XM_047441405.1	c.*9G>A		3_prime_UTR_variant	10/10
UPB1	XR_001755249.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPB1	ENST00000326010.10	c.977G>A	p.Arg326Gln	missense_variant	9/10	1	NM_016327.3	P1
UPB1	ENST00000498140.1	n.273G>A		non_coding_transcript_exon_variant	3/4	1
UPB1	ENST00000486043.1	n.399G>A		non_coding_transcript_exon_variant	3/3	3
UPB1	ENST00000415388.5	c.*676G>A		3_prime_UTR_variant, NMD_transcript_variant	8/9	5

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152252 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00194 AC: 488 AN: 251452 Hom.: 10 AF XY: 0.00182 AC XY: 248 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0253

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000564 AC: 825 AN: 1461882 Hom.: 11 Cov.: 32 AF XY: 0.000562 AC XY: 409 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0170

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152370 Hom.: 4 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74524

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0254

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00176 AC: 214

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of beta-ureidopropionase Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
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 provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 326 of the UPB1 protein (p.Arg326Gln). This variant is present in population databases (rs118163237, gnomAD 2.6%). This missense change has been observed in individual(s) with beta-ureidopropionase deficiency (PMID: 22525402, 25236466, 25445412). ClinVar contains an entry for this variant (Variation ID: 225511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt UPB1 protein function. Experimental studies have shown that this missense change affects UPB1 function (PMID: 22525402, 24526388). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2017	The R326Q variant has been seen in both the homozygous and heterozygous states (along with a second UPB1 variant) in multiple individuals with beta-ureidopropionase deficiency (Nakajima et al., 2014; Shu et al., 2014). The R326Q variant is the most commonly reported variant associated with beta-ureidopropionase deficiency, with a carrier frequency of 2.8% in the Northern Chinese population and 1.8% in the Japanese population (Nakajima et al., 2014; Shu et al., 2014). Functional studies have shown that expression of beta-ureidopropionase constructs containing the R326Q variant yield little or no beta-ureidopropionase activity (Nakajima et al., 2014; van Kuilenburg et al., 2012). The R326Q variant is a semi-conservative amino acid substitution at a position that is conserved across species. However, the R326Q variant is observed in 202/8648 (2.3%) alleles from individuals of East Asian background, including four homozygous individuals, in the ExAC data set (Lek et al., 2016). We have also identified unaffected individuals who are homozygous for the R326Q variant at GeneDx. As the R326Q variant is observed in the homozygous state among unaffected individuals in the ExAC data set and at GeneDx, we interpret R326Q as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2020

The p.Arg326Gln variant in UPB1 has been reported in at least 12 homozygous and 6 compound heterozygous individuals with Beta-ureidopropionase deficiency and segregated with this biochemical phenotype in 1 affected individual from 1 family (van Kuilenburg 2012 PMID: 22525402, Nakajima 2014 PMID: 24526388, Shu 2104 PMID: 25236466,Lam 2015 25445412, Akiyama 2017 PMID: 27553092, Mak 2018 PMID 30109123). However, this variant has also been identified in 2.6%% (521/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has also been reported in ClinVar (Variation ID 225511). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Nakajima 2014 PMID: 24526388); however, these types of assays may not accurately represent biological function and homozygous individuals, though clearly deficient in Beta-ureidopropionase deficiency exhibit a wide range of phenotypes (from asymptomatic to neurological or digestive system) suggesting other factors might also be involved. In summary, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.80
Sift	Benign	0.29	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.94
MVP		0.93
MPC		0.61
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.85
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs118163237; hg19: chr22-24919647; COSMIC: COSV58112675;