X-38369882-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000531.6(OTC):c.298+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,152,072 control chromosomes in the GnomAD database, including 1 homozygotes. There are 160 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., 21 hem., cov: 23)

Exomes 𝑓: 0.00041 ( 0 hom. 139 hem. )

Consequence

OTC
NM_000531.6 splice_region, intron

Scores

Splicing: ADA: 0.5275

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:9

Conservation

PhyloP100: 1.29

Publications

6 publications found

Variant links:

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]

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:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant X-38369882-G-C is Benign according to our data. Variant chrX-38369882-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000677 (76/112240) while in subpopulation EAS AF = 0.0203 (73/3593). AF 95% confidence interval is 0.0166. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 21 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.298+5G>C		splice_region intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.298+5G>C		splice_region intron	N/A	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.298+5G>C	splice_region intron	N/A	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-296239G>C	intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.298+5G>C	splice_region intron	N/A	ENSP00000519059.1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

AN:

112191

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0202

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00162

AC:

296

AN:

183053

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0211

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000664

GnomAD4 exome

AF:

0.000406

AC:

422

AN:

1039832

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

139

AN XY:

313636

show subpopulations

African (AFR)

AF:

0.000118

AC:

AN:

25359

American (AMR)

AF:

0.0000285

AC:

AN:

35110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18988

East Asian (EAS)

AF:

0.0117

AC:

350

AN:

29923

South Asian (SAS)

AF:

0.000190

AC:

AN:

52751

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3994

European-Non Finnish (NFE)

AF:

0.00000760

AC:

AN:

789090

Other (OTH)

AF:

0.00118

AC:

AN:

44193

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000677

AC:

AN:

112240

Hom.:

Cov.:

AF XY:

0.000610

AC XY:

AN XY:

34402

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30936

American (AMR)

AF:

0.0000946

AC:

AN:

10574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.0203

AC:

AN:

3593

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53308

Other (OTH)

AF:

0.00

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:1Benign:5

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 27, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Apr 03, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Aug 28, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Pathogenic:1

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Inborn genetic diseases

Benign:1

Nov 09, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

OTC-related disorder

Benign:1

Apr 21, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.3

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.50

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.37

Position offset: -5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over