rs749748052

Positions:

• chrX-38352591-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001407092.1(OTC):​c.-79-27C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000336 in 595,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000021 (0 hom. 1 hem.)
• Consequence: OTC NM_001407092.1 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.04

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352591-C-A is Pathogenic according to our data. Variant chrX-38352591-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 487338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_001407092.1	c.-79-27C>A		intron_variant			NP_001394021.1
OTC	NM_000531.6			upstream_gene_variant		ENST00000039007.5	NP_000522.3
OTC	XM_017029556.2			upstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000643344.1	c.-106C>A		5_prime_UTR_variant, NMD_transcript_variant	1/11			ENSP00000496606
OTC	ENST00000039007.5			upstream_gene_variant		1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111786 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33946

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 1 AN: 483418 Hom.: 0 Cov.: 7 AF XY: 0.00000642 AC XY: 1 AN XY: 155650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000336

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111840 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34010

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Caldovic Lab, Children's National Health System	Dec 12, 2017	The patient had clinical and biochemical symptoms of OTC deficiency, and no disease causing sequence variants in the OTC coding sequence and canonical splice sites. Functional testing in cultured cells indicates reduced expression of reporter gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	This variant occurs in a non-coding region of the OTC gene. It does not change the encoded amino acid sequence of the OTC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 29282796, 35605046; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 487338). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects OTC function (PMID: 29282796, 35605046). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Elsea Laboratory, Baylor College of Medicine	May 13, 2024	The c.-106C>A variant in the OTC gene is located in the 5'UTR. This variant has been observed in multiple individuals with late-onset ornithine transcarbamylase deficiency (PMID: 29282796, 35605046, 35822098). This variant has been reported as a common ancestral allele in a large Utahn kinship (PMID: 35605046; https://www.janewrightearlotc.com/). This variant is rare in the gnomAD population database. This variant is located immediately adjacent to the HNF4 transcription factor binding site and functional studies have shown that this variant affects HNF4 binding. In HepG2 cells transfected with c.-106C>A plasmid, the relative lucierase actiivty was lower as compared to wild typer promoter sequence containing plasmid. Therefore, the c.-106C>A variant in OTC gene is classified as pathogenic for late-onset OTC deficiency. ACMG variant classification evidence codes: PS4+PS3+PP4+PP1 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2024	Observed in hemizygous state in two individuals with late onset OTC deficiency; also reported in an asymptomatic adult male whose brother died from hyperammonemic encephalopathy and suspected OTCD; segregation studies for this variant in the affected brother were not possible (PMID: 29282796); Published functional studies demonstrate a damaging effect as the variant was shown to reduce promoter activity to approximately 10% or 27% of wildtype in absence or presence of enhancer; authors concluded that the mild effect of this variant was the reason for the late onset and incomplete penetrance (PMID: 35605046); No data available from control populations to assess the frequency of this variant; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 35605046, Sonier[article]2022, 35822098, 35734906, 29282796) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 14, 2024	The OTC c.-106C>A variant (rs749748052; ClinVar Variation ID: 487338) occurs at a moderately conserved nucleotide located in the 5' untranslated region of the OTC gene and is localized in a HNF4a transcription factor binding site (Luksan 2014). In vitro transfection of reporter constructs harboring c.-106C>A into liver-derived cell lines demonstrate mild to moderate reduction in OTC expression (Han 2022, Jang 2018). This variant is reported in a single female individual in the 1000 Genomes Project (1/3775 alleles) but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. It has been described in multiple males affected with late-onset OTC deficiency and in several heterozygotes with positive allopurinol test results (Finkelstein 1990, Jang 2018, Hertzog 2022, Han 2022). In testing performed both in published studies and at ARUP Laboratories, this variant has been identified in multiple hemizygotes from a large, multigenerational kindred separated by many meioses (Finkelstein 1990, Jang 2018). Although this variant has also been observed in multiple asymptomatic male relatives (Jang 2018; ARUP Laboratories), since c.-106C>A is located in a regulatory site, it is likely that hemizygotes are less susceptible to stressors precipitating a hyperammonemic crisis than patients harboring pathogenic coding sequence variants. Based on available information, this variant is considered to be pathogenic for late onset OTC with incomplete penetrance. References: Finkelstein JE et al. Late-onset ornithine transcarbamylase deficiency in male patients. J Pediatr. 1990 Dec;117(6):897-902. PMID: 2246687. Han ST et al. A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia. J Inherit Metab Dis. 2022 Jul;45(4):710-718. PMID: 35605046. Hertzog A et al. A serendipitous journey to a promoter variant: The c.-106C>A variant and its role in late-onset ornithine transcarbamylase deficiency. JIMD Rep. 2022 Apr 12;63(4):271-275. PMID: 35822098. Jang Y et al. Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene. Hum Mutat. 2018 Apr;39(4):527-536. PMID: 29282796. Luksan O et al. HNF-4alpha regulates expression of human ornithin carbamoyltransferase through interaction with two positive cis-acting regulatory elements located in the proximal promoter. Folia Biol (Praha). 2014;60(3):133-43. PMID: 25056436. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs749748052; hg19: chrX-38211844;