X-38352581-C-T

Variant names:

• chrX-38352581-C-T
• rs1555971006
• ENST00000465127.1:c.172-313540C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001407092.1(OTC):​c.-79-37C>T variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_001407092.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.99

Genes affected

ENSG00000250349 (HGNC:):

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_001407092.1	c.-79-37C>T		intron_variant	Intron 2 of 11		NP_001394021.1
OTC	NM_000531.6	c.-116C>T		upstream_gene_variant		ENST00000039007.5	NP_000522.3
OTC	XM_017029556.2	c.-116C>T		upstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-313540C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000039007.5	c.-116C>T		upstream_gene_variant		1	NM_000531.6	ENSP00000039007.4
OTC	ENST00000488812.1	n.-24C>T		upstream_gene_variant		5
OTC	ENST00000643344.1	n.-116C>T		upstream_gene_variant				ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1 Uncertain:1

Jul 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant occurs in a non-coding region of the OTC gene. It does not change the encoded amino acid sequence of the OTC protein. This variant has been observed in individual(s) with clinical features of OTC deficiency (PMID: 29282796; Invitae). 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. Studies have shown that this variant alters OTC gene expression (PMID: 29282796). ClinVar contains an entry for this variant (Variation ID: 487343). -

Dec 12, 2017

Caldovic Lab, Children's National Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The patient had clinical and biochemical symptoms of OTC deficiency, and no disease causing sequence variants in the OTC coding sequence and canonical splice sites. Functional testing in cultured cells indicates reduced expression of reporter gene. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555971006; hg19: chrX-38211834;