22-24525738-C-G

Variant names:

• chr22-24525738-C-G
• rs542324398
• NM_016327.3:c.1099C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016327.3(UPB1):​c.1099C>G​(p.Arg367Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UPB1 NM_016327.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55
• Publications: 2 publications found

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]

UPB1 Gene-Disease associations (from GenCC):

• beta-ureidopropionase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19992092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016327.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPB1	NM_016327.3	MANE Select	c.1099C>G	p.Arg367Gly	missense	Exon 10 of 10	NP_057411.1	Q9UBR1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPB1	ENST00000326010.10	TSL:1 MANE Select	c.1099C>G	p.Arg367Gly	missense	Exon 10 of 10	ENSP00000324343.5	Q9UBR1
	UPB1	ENST00000498140.1	TSL:1	n.395C>G		non_coding_transcript_exon	Exon 4 of 4
	UPB1	ENST00000858218.1		c.1231C>G	p.Arg411Gly	missense	Exon 11 of 11	ENSP00000528277.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of beta-ureidopropionase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.73	N
PhyloP100		2.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.044	D
Polyphen		0.088	B
Vest4		0.20
MutPred		0.54		Gain of helix (P = 0.0225)
MVP		0.79
MPC		0.17
ClinPred		0.81	D
GERP RS		3.5
Varity_R		0.22
gMVP		0.62
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs542324398; hg19: chr22-24921706;