rs118163237

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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).

Frequency

Genomes: 𝑓 0.00095 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 11 hom. )

Consequence

UPB1
NM_016327.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 9.74

Variant links:

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]

UPB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPB1	NM_016327.3 link	c.977G>A	p.Arg326Gln	missense_variant	Exon 9 of 10	ENST00000326010.10	NP_057411.1	Q9UBR1A0A024R1H3B3KNC1
UPB1	XM_047441404.1 link	c.1015G>A	p.Gly339Arg	missense_variant	Exon 10 of 10		XP_047297360.1
UPB1	XM_047441405.1 link	c.*9G>A		3_prime_UTR_variant	Exon 10 of 10		XP_047297361.1
UPB1	XR_001755249.2 link	n.*39G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPB1	ENST00000326010.10 link	c.977G>A	p.Arg326Gln	missense_variant	Exon 9 of 10	1	NM_016327.3	ENSP00000324343.5		Q9UBR1

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

144

AN:

152252

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00182

AC XY:

248

AN XY:

135900

show subpopulations

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.:

Cov.:

AF XY:

0.000562

AC XY:

409

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74524

show subpopulations

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.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00176

AC:

214

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of beta-ureidopropionase

Uncertain:3Benign:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 19, 2023

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Jan 30, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jun 19, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.80

Sift

Benign

0.29

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.94

MVP

0.93

MPC

0.61

ClinPred

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over