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 no assertion criteria provided P:1
• 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 id is 97304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.718-2_731delAGAATGGTACCAAGCT	p.Asn240fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.718-2_731delAGAATGGTACCAAGCT	p.Asn240fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 12		NP_001394021.1
OTC	XM_017029556.2	c.718-2_731delAGAATGGTACCAAGCT	p.Asn240fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.718-5_728delGCTAGAATGGTACCAA	p.Asn240fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257250_172-257235delGCTAGAATGGTACCAA		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

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:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;