rs1555972540

Positions:

• chrX-38369878-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000039007.5(OTC):​c.298+2dup variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC ENST00000039007.5 splice_donor
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07605634 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 0 (no position change), new splice context is: cagGTtaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.298+2dup		splice_donor_variant		ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.298+2dup		splice_donor_variant			NP_001394021.1
OTC	XM_017029556.2	c.298+2dup		splice_donor_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.298+2dup		splice_donor_variant		1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000643344.1	c.298+2dup		splice_donor_variant, NMD_transcript_variant				ENSP00000496606
OTC	ENST00000488812.1	n.353+39dup		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with OTC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 3 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein, but it affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555972540; hg19: chrX-38229131;