rs72558484

Variant names:

• chrX-38412001-T-C
• rs72558484
• NM_000531.6:c.1005+2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000531.6(OTC):​c.1005+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.59

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12957746 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-38412001-T-C is Pathogenic according to our data. Variant chrX-38412001-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 97090.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.1005+2T>C		splice_donor_variant, intron_variant	Intron 9 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.1005+2T>C		splice_donor_variant, intron_variant	Intron 11 of 11		NP_001394021.1
OTC	XM_017029556.2	c.*140T>C		downstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.1005+2T>C		splice_donor_variant, intron_variant	Intron 9 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-254120T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*755+2T>C		splice_donor_variant, intron_variant	Intron 10 of 10			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Oct 23, 2019

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico splice prediction tools (ASSP and NNSPLICE) suggest that this variant might affect splicing due to the loss of essential donor site and introduction of a new splice site, which in turn might lead to a frameshift and consequent premature termination of the protein; this will likely result in loss-of-function. This variant (also known as IVS9+2T>C) was previously reported as a deleterious mutation in association with acute neonatal hyperammonemia. In addition, all the mutations in consensus splicing sites identified in the study including IVS9+2T>C, are reported to confer a neonatal phenotype [PMID: 11793468]. -

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
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		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: rs72558484; hg19: chrX-38271254;