chrX-38352260-T-C

Variant names:

• chrX-38352260-T-C
• ENST00000465127.1:c.172-313861T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000465127.1(ENSG00000250349):​c.172-313861T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ENSG00000250349 ENST00000465127.1 intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_001407092.1	c.-79-358T>C		intron_variant	Intron 2 of 11		NP_001394021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-313861T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000713758.1	c.-79-358T>C		intron_variant	Intron 2 of 11			ENSP00000519059.1
OTC	ENST00000713759.1	c.-88-15031T>C		intron_variant	Intron 1 of 9			ENSP00000519060.1
OTC	ENST00000713760.1	n.-79-358T>C		intron_variant	Intron 2 of 12			ENSP00000519061.1

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

OTC-related disorder Uncertain:1

Dec 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OTC c.-437T>C variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Other variants in the pre-coding region of OTC have been reported in individuals with ornithine transcarbamylase deficiency but no identified sequence variant in the exon or exon/intron boundary regions of the OTC gene (Jang et al. 2018. PubMed ID: 29282796). Several of these variants were reported to reduce reported gene expression in an in vitro study (Jang et al. 2018. PubMed ID: 29282796). At this time, the clinical significance of the c.-437T>C variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		1.7
PromoterAI		-0.0012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chrX-38211513;