Variant chrX-38352591-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.04

Variant links:

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]

OTC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	MANE	Protein
OTC	NM_001407092.1 linkuse as main transcript	c.-79-27C>A	intron_variant		NP_001394021.1
OTC	NM_000531.6 linkuse as main transcript		upstream_gene_variant	ENST00000039007.5	NP_000522.3
OTC	XM_017029556.2 linkuse as main transcript		upstream_gene_variant		XP_016885045.1

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33946

show subpopulations

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:

AN:

483418

Hom.:

Cov.:

AF XY:

0.00000642

AC XY:

AN XY:

155650

show subpopulations

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:

AN:

111840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34010

show subpopulations

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

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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