Genetic Variant ENSG00000250349:c.172-313567T>C (chrX-38352554-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000465127.1(ENSG00000250349):c.172-313567T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 394,385 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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)

Exomes 𝑓: 0.0000025 ( 0 hom. 0 hem. )

Consequence

ENSG00000250349
ENST00000465127.1 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.432

Publications

0 publications found

Variant links:

Genes affected

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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

OTC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.58).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_001407092.1 link	c.-79-64T>C	intron_variant	Intron 2 of 11		NP_001394021.1
OTC	NM_000531.6 link	c.-143T>C	upstream_gene_variant		ENST00000039007.5	NP_000522.3	P00480
OTC	XM_017029556.2 link	c.-143T>C	upstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1 link	c.172-313567T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171
OTC	ENST00000039007.5 link	c.-143T>C		upstream_gene_variant		1	NM_000531.6	ENSP00000039007.4		P00480

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000254

AC:

AN:

394385

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

131019

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

12100

American (AMR)

AF:

0.00

AC:

AN:

25821

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13420

East Asian (EAS)

AF:

0.00

AC:

AN:

22946

South Asian (SAS)

AF:

0.00

AC:

AN:

35187

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1662

European-Non Finnish (NFE)

AF:

0.00000429

AC:

AN:

233115

Other (OTH)

AF:

0.00

AC:

AN:

22180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:1

May 16, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a T to C nucleotide substition at the -143 position in the 5' untranslated region of the OTC gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with OTC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring in the 5' untranslated region of the OTC gene have been reported to be pathogenic (PMID: 29282796). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.43

PromoterAI

-0.030

Neutral

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over