rs34035085

chr22-24500256-C-Achr22-24500256-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016327.3(UPB1):c.254C>A(p.Ala85Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,614,192 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A85T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: UPB1 NM_016327.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3 O:1
• Conservation: PhyloP100: 6.59

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069878697).
• BP6: Variant 22-24500256-C-A is Benign according to our data. Variant chr22-24500256-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4149.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, not_provided=1, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00427 (650/152324) while in subpopulation AFR AF= 0.0139 (577/41568). AF 95% confidence interval is 0.0129. There are 5 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPB1	NM_016327.3	c.254C>A	p.Ala85Glu	missense_variant	2/10	ENST00000326010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPB1	ENST00000326010.10	c.254C>A	p.Ala85Glu	missense_variant	2/10	1	NM_016327.3	P1
UPB1	ENST00000382760.2	c.254C>A	p.Ala85Glu	missense_variant	2/4	5
UPB1	ENST00000415388.5	c.105-1870C>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152206 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 251072 Hom.: 1 AF XY: 0.000862 AC XY: 117 AN XY: 135772

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461868 Hom.: 5 Cov.: 32 AF XY: 0.000419 AC XY: 305 AN XY: 727236

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152324 Hom.: 5 Cov.: 33 AF XY: 0.00442 AC XY: 329 AN XY: 74496

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.000683 Hom.: 3

Bravo AF: 0.00551

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	UPB1: BP4, BS1, BS2 -

Deficiency of beta-ureidopropionase Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2004	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.5% in african population, also present in other populations in ExAC -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0070	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.1e-8	A;A;A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.068	T;D
Sift4G	Benign	0.094	T;D
Polyphen		0.46	P;.
Vest4		0.57
MVP		0.72
MPC		0.19
ClinPred		0.040	T
GERP RS		4.7
Varity_R		0.31
gMVP		0.73

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: rs34035085; hg19: chr22-24896224;