22-24495441-T-G

Variant names:

• chr22-24495441-T-G
• rs200688546
• NM_016327.3:c.38T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016327.3(UPB1):​c.38T>G​(p.Leu13Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UPB1 NM_016327.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPB1	NM_016327.3	c.38T>G	p.Leu13Trp	missense_variant	Exon 1 of 10	ENST00000326010.10	NP_057411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPB1	ENST00000326010.10	c.38T>G	p.Leu13Trp	missense_variant	Exon 1 of 10	1	NM_016327.3	ENSP00000324343.5
UPB1	ENST00000382760.2	c.38T>G	p.Leu13Trp	missense_variant	Exon 1 of 4	5		ENSP00000372208.2
UPB1	ENST00000415388.5	n.38T>G		non_coding_transcript_exon_variant	Exon 1 of 9	5		ENSP00000400684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250224 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461374 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.000173 AC: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.62	D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.32		Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);
MVP		0.95
MPC		0.73
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.90

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: rs200688546; hg19: chr22-24891409;