rs72558427

Variant names:

• chrX-38403742-T-C
• rs72558427
• NM_000531.6:c.663+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.663+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 splice_donor, intron
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.91
• Publications: 0 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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.115492955 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38403742-T-C is Pathogenic according to our data. Variant chrX-38403742-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.663+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.663+2T>C		splice_donor_variant, intron_variant	Intron 8 of 11		NP_001394021.1
OTC	XM_017029556.2	c.663+2T>C		splice_donor_variant, intron_variant	Intron 6 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.663+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262379T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 10, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ornithine carbamoyltransferase deficiency Pathogenic:1

Apr 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 97285). Disruption of this splice site has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 9266388). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 of the OTC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.9
GERP RS		5.9
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -2

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

Other links and lift over

dbSNP: rs72558427; hg19: chrX-38262995; COSMIC: COSV99234054; COSMIC: COSV99234054;