rs72552300

Positions:

• chrX-38352763-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.67C>T​(p.Arg23Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.99

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 414 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352763-C-T is Pathogenic according to our data. Variant chrX-38352763-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.67C>T	p.Arg23Ter	stop_gained	1/10	ENST00000039007.5
OTC	NM_001407092.1	c.67C>T	p.Arg23Ter	stop_gained	3/12
OTC	XM_017029556.2	c.67C>T	p.Arg23Ter	stop_gained	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.67C>T	p.Arg23Ter	stop_gained	1/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.159C>T		non_coding_transcript_exon_variant	1/6	5
OTC	ENST00000643344.1	c.67C>T	p.Arg23Ter	stop_gained, NMD_transcript_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 97292). This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 1671317, 18604903). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg23*) in the OTC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 01, 2021	The OTC c.67C>T; p.Arg23Ter variant (rs72552300) is reported in the literature in individuals affected with ornithine transcarbamylase deficiency (Grompe 1991, Wilnai 2018). This variant is reported in ClinVar (Variation ID: 97292), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Grompe M et al. Improved molecular diagnostics for ornithine transcarbamylase deficiency. Am J Hum Genet. 1991 Feb;48(2):212-22. Wilnai Y et al. Prenatal treatment of ornithine transcarbamylase deficiency. Mol Genet Metab. 2018 Mar;123(3):297-300. -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10946359, 24485820, 1671317, 18604903, 29396029, 9286441, 11793468, 11117428, 25433810, 19138872, 33489762, 33309754, 33272297, 32778825) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A
Vest4		0.77
GERP RS		4.9

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: rs72552300; hg19: chrX-38212016; COSMIC: COSV50001813;