22-24495387-A-T

Position:

• chr22-24495387-A-T

Variant summary

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

The NM_016327.3(UPB1):​c.-17A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,612,114 control chromosomes in the GnomAD database, including 20,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1399 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19455 hom.)
• Consequence: UPB1 NM_016327.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -4.86

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 22-24495387-A-T is Benign according to our data. Variant chr22-24495387-A-T is described in ClinVar as [Benign]. Clinvar id is 100155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPB1	NM_016327.3	c.-17A>T		5_prime_UTR_variant	1/10	ENST00000326010.10	NP_057411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPB1	ENST00000326010.10	c.-17A>T		5_prime_UTR_variant	1/10	1	NM_016327.3	ENSP00000324343	P1
UPB1	ENST00000382760.2	c.-17A>T		5_prime_UTR_variant	1/4	5		ENSP00000372208
UPB1	ENST00000415388.5	c.-17A>T		5_prime_UTR_variant, NMD_transcript_variant	1/9	5		ENSP00000400684

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18213 AN: 152182 Hom.: 1399 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.151 AC: 37600 AN: 248926 Hom.: 3254 AF XY: 0.154 AC XY: 20804 AN XY: 134840

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.159 AC: 232483 AN: 1459814 Hom.: 19455 Cov.: 33 AF XY: 0.160 AC XY: 116444 AN XY: 726304

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0619

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.120 AC: 18208 AN: 152300 Hom.: 1399 Cov.: 32 AF XY: 0.121 AC XY: 9020 AN XY: 74466

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.0688

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.101

Alfa AF: 0.126 Hom.: 253

Bravo AF: 0.108

Asia WGS AF: 0.206 AC: 718 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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -

Deficiency of beta-ureidopropionase Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	0.10
DANN	Benign	0.50

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: rs2070475; hg19: chr22-24891355; COSMIC: COSV58113975; COSMIC: COSV58113975;