rs1555975756

chrX-38401693-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-38401693-G-A is Pathogenic according to our data. Variant chrX-38401693-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449382.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Uncertain_significance=1}. 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	UniProt
OTC	NM_000531.6	c.540+265G>A		intron_variant		ENST00000039007.5
OTC	NM_001407092.1	c.540+265G>A		intron_variant
OTC	XM_017029556.2	c.540+265G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.540+265G>A		intron_variant		1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*290+265G>A		intron_variant, NMD_transcript_variant
OTC	ENST00000488812.1	n.577+265G>A		intron_variant, non_coding_transcript_variant		5

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:7 Uncertain:1

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	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	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	Invitae	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2016

The c.540+265 G>A variant in the OTC gene has been reported previously in association with neonatal onset ornithine transcarbamylase (OTC) deficiency in hemizygous males (Ogino et al. 2007; Engel et al. 2008). mRNA analysis of c.540+265 G>A found that this variant results in an insertion of 135 bases in intron 5, creates a new splice acceptor site and leads to the creation of a new in-frame Stop codon, which causes loss of normal protein function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008). The c.540+265 G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In summary, we interpret c.540+265 G>A to be a pathogenic variant, and its presence is consistent with the diagnosis of OTC deficiency in this individual. Approximately 20% of females who are heterozygous for variants in the OTC gene are clinically symptomatic with disease severity similar to males with partial deficiency (Yamaguchi et al., 2006; Tuchman et al., 2002). -

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;