rs73196229

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000039007.5(OTC):c.299-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,121,538 control chromosomes in the GnomAD database, including 16,616 homozygotes. There are 61,679 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1374 hom., 4103 hem., cov: 22)

Exomes 𝑓: 0.19 ( 15242 hom. 57576 hem. )

Consequence

OTC
ENST00000039007.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001725

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.103

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-38381334-T-A is Benign according to our data. Variant chrX-38381334-T-A is described in ClinVar as [Benign]. Clinvar id is 93220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38381334-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
OTC	NM_000531.6 linkuse as main transcript	c.299-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1 linkuse as main transcript	c.299-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001394021.1
OTC	XM_017029556.2 linkuse as main transcript	c.299-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
OTC	ENST00000039007.5 linkuse as main transcript	c.299-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000643344.1 linkuse as main transcript	c.*49-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant			ENSP00000496606
OTC	ENST00000488812.1 linkuse as main transcript	n.354-26T>A	intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

16397

AN:

110242

Hom.:

1375

Cov.:

AF XY:

0.126

AC XY:

4101

AN XY:

32522

show subpopulations

Gnomad AFR

AF:

0.0354

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.000556

Gnomad SAS

AF:

0.0341

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.227

Gnomad OTH

AF:

0.167

GnomAD3 exomes

AF:

0.150

AC:

24614

AN:

164322

Hom.:

1696

AF XY:

0.147

AC XY:

8325

AN XY:

56670

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.0901

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.000320

Gnomad SAS exome

AF:

0.0447

Gnomad FIN exome

AF:

0.163

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.195

AC:

196936

AN:

1011239

Hom.:

15242

Cov.:

AF XY:

0.187

AC XY:

57576

AN XY:

307349

show subpopulations

Gnomad4 AFR exome

AF:

0.0364

Gnomad4 AMR exome

AF:

0.0994

Gnomad4 ASJ exome

AF:

0.275

Gnomad4 EAS exome

AF:

0.000468

Gnomad4 SAS exome

AF:

0.0502

Gnomad4 FIN exome

AF:

0.170

Gnomad4 NFE exome

AF:

0.220

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.149

AC:

16389

AN:

110299

Hom.:

1374

Cov.:

AF XY:

0.126

AC XY:

4103

AN XY:

32589

show subpopulations

Gnomad4 AFR

AF:

0.0353

Gnomad4 AMR

AF:

0.127

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.000558

Gnomad4 SAS

AF:

0.0334

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.227

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.138

Hom.:

1097

Bravo

AF:

0.148

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2019	Variant summary: OTC c.299-8T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.15 in 181703 control chromosomes in the gnomAD database, including 1881 homozygotes and 9206 hemizygotes. The observed variant frequency is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTC causing Ornithine Transcarbamylase Deficiency phenotype (0.0046), strongly suggesting that the variant is benign. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Ornithine carbamoyltransferase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.9

DANN

Benign

0.83

BranchPoint Hunter

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over