22-24495485-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_016327.3(UPB1):c.82G>A(p.Val28Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,614,064 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: UPB1 NM_016327.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.193

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042829514).
• BP6: Variant 22-24495485-G-A is Benign according to our data. Variant chr22-24495485-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 781613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00204 (310/152318) while in subpopulation AFR AF= 0.00709 (295/41582). AF 95% confidence interval is 0.00643. There are 1 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPB1	NM_016327.3	c.82G>A	p.Val28Ile	missense_variant	1/10	ENST00000326010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPB1	ENST00000326010.10	c.82G>A	p.Val28Ile	missense_variant	1/10	1	NM_016327.3	P1
UPB1	ENST00000382760.2	c.82G>A	p.Val28Ile	missense_variant	1/4	5
UPB1	ENST00000415388.5	c.82G>A	p.Val28Ile	missense_variant, NMD_transcript_variant	1/9	5

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

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: 0.00239

GnomAD3 exomes AF: 0.000555 AC: 139 AN: 250406 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135442

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461746 Hom.: 3 Cov.: 32 AF XY: 0.000257 AC XY: 187 AN XY: 727170

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74478

Gnomad4 AFR AF: 0.00709

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000348 Hom.: 1

Bravo AF: 0.00225

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000659 AC: 80

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of beta-ureidopropionase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.77
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.043
MVP		0.31
MPC		0.096
ClinPred		0.014	T
GERP RS		0.39
Varity_R		0.021
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141896929; hg19: chr22-24891453; COSMIC: COSV58115750; COSMIC: COSV58115750;