rs1555975756

Variant names:

• chrX-38401693-G-A
• rs1555975756
• NM_000531.6:c.540+265G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000617478: Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.539
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617478: 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); SCV004357050: 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).; SCV004834032: 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).; SCV005900547: Functional studies demonstrated that the c.540+265G>A variant results in decreased enzyme levels (PMID: 34014569).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 Pathogenic. ClinVar VariationId is 449382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.540+265G>A		intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.540+265G>A		intron	N/A	NP_001394021.1	P00480

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.540+265G>A		intron	N/A	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-264428G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.540+265G>A		intron	N/A	ENSP00000519059.1	P00480

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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Ornithine carbamoyltransferase deficiency (10)
1	-	-	not provided (1)
1	-	-	Protein avoidance;C4023070:Abnormal circulating ornithine concentration;C5574662:Hyperammonemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	22
DANN	Benign	0.36
PhyloP100		0.54
Mutation Taster		=38/62	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555975756; hg19: chrX-38260946;