rs72558434

Variant names:

• chrX-38408870-TGCTAGAATGGTACCAA-T
• rs72558434
• NM_000531.6:c.718-2_731delAGAATGGTACCAAGCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000531.6(OTC):​c.718-2_731delAGAATGGTACCAAGCT​(p.Asn240fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.77
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-38408870-TGCTAGAATGGTACCAA-T is Pathogenic according to our data. Variant chrX-38408870-TGCTAGAATGGTACCAA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 97304.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.718-2_731delAGAATGGTACCAAGCT	p.Asn240fs	frameshift splice_acceptor splice_region intron	Exon 8 of 10	NP_000522.3
	OTC	NM_001407092.1		c.718-2_731delAGAATGGTACCAAGCT	p.Asn240fs	frameshift splice_acceptor splice_region intron	Exon 10 of 12	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.718-5_728delGCTAGAATGGTACCAA	p.Asn240fs	frameshift splice_acceptor splice_region intron	Exon 8 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257250_172-257235delGCTAGAATGGTACCAA		intron	N/A	ENSP00000417050.1
	OTC	ENST00000643344.1		n.*468-5_*478delGCTAGAATGGTACCAA		splice_region non_coding_transcript_exon	Exon 9 of 11	ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Apr 04, 2025

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000531.5(OTC):c.718-2_731del16 is a variant in a canonical splice site classified as pathogenic in the context of ornithine transcarbamylase deficiency. c.718-2_731del16 has been observed in a case with relevant disease (PMID: 16786505). Relevant functional assessments of this variant are not available in the literature. c.718-2_731del16 has not been observed in referenced population frequency databases. In summary, NM_000531.5(OTC):c.718-2_731del16 is a variant in a canonical splice site in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

not provided Pathogenic:1

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs72558434; hg19: chrX-38268123;