chr22-24495324-C-G

Variant names:

• chr22-24495324-C-G
• rs2070474
• ENST00000382760:c.-80C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000382760(UPB1):​c.-80C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,467,332 control chromosomes in the GnomAD database, including 252,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27783 hom., cov: 34)
  • Exomes 𝑓: 0.58 (224426 hom.)
• Consequence: UPB1 ENST00000382760 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.981

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-24495324-C-G is Benign according to our data. Variant chr22-24495324-C-G is described in ClinVar as [Benign]. Clinvar id is 100154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPB1	NM_016327.3	c.-80C>G		upstream_gene_variant		ENST00000326010.10	NP_057411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPB1	ENST00000382760	c.-80C>G		5_prime_UTR_variant	Exon 1 of 4	5		ENSP00000372208.2
UPB1	ENST00000415388.5	n.-80C>G		non_coding_transcript_exon_variant	Exon 1 of 9	5		ENSP00000400684.1
UPB1	ENST00000415388.5	n.-80C>G		5_prime_UTR_variant	Exon 1 of 9	5		ENSP00000400684.1
UPB1	ENST00000326010.10	c.-80C>G		upstream_gene_variant		1	NM_016327.3	ENSP00000324343.5

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91151 AN: 152034 Hom.: 27732 Cov.: 34

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.611

GnomAD4 exome AF: 0.580 AC: 762792 AN: 1315180 Hom.: 224426 Cov.: 20 AF XY: 0.572 AC XY: 378879 AN XY: 661802

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.620

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.561

Gnomad4 NFE exome AF: 0.598

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.600 AC: 91262 AN: 152152 Hom.: 27783 Cov.: 34 AF XY: 0.593 AC XY: 44136 AN XY: 74378

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.595

Gnomad4 OTH AF: 0.608

Alfa AF: 0.607 Hom.: 2665

Bravo AF: 0.615

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

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Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Deficiency of beta-ureidopropionase Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2070474; hg19: chr22-24891292; COSMIC: COSV58113479; COSMIC: COSV58113479;