rs1555975756

Positions:

• chrX-38401693-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.540+265G>A variant causes a intron 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.539

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38401693-G-A is Pathogenic according to our data. Variant chrX-38401693-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 449382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38401693-G-A is described in Lovd as [Pathogenic]. Variant chrX-38401693-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.540+265G>A		intron_variant		ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.540+265G>A		intron_variant			NP_001394021.1
OTC	XM_017029556.2	c.540+265G>A		intron_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.540+265G>A		intron_variant		1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-264428G>A		intron_variant		5		ENSP00000417050.1
OTC	ENST00000488812.1	n.577+265G>A		intron_variant		5
OTC	ENST00000643344.1	n.*290+265G>A		intron_variant				ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 449382). This variant has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 18204299, 18440262, 33489762). 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 sequence change falls in intron 5 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2022

Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 18440262, 34014569, 19823873, 28771251, 33272297, 33489762, 18204299) -

Protein avoidance;C4023070:Abnormal circulating ornithine concentration;C5574662:Hyperammonemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	22
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555975756; hg19: chrX-38260946;