rs73196229

Variant names:

• chrX-38381334-T-A
• rs73196229
• NM_000531.6:c.299-8T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38381334-T-A
• chrX-38381334-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000531.6(OTC):​c.299-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 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 NM_000531.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001725
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.103
• Publications: 8 publications found

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

ENSG00000250349 (HGNC:):

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId is 93220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.299-8T>A		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.299-8T>A		splice_region_variant, intron_variant	Intron 5 of 11		NP_001394021.1
OTC	XM_017029556.2	c.299-8T>A		splice_region_variant, intron_variant	Intron 3 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.299-8T>A		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-284787T>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 16397 AN: 110242 Hom.: 1375 Cov.: 22

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

GnomAD2 exomes AF: 0.150 AC: 24614 AN: 164322 AF XY: 0.147

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 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.: 20 AF XY: 0.187 AC XY: 57576 AN XY: 307349

African (AFR) AF: 0.0364 AC: 873 AN: 24003

American (AMR) AF: 0.0994 AC: 3033 AN: 30517

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 4995 AN: 18143

East Asian (EAS) AF: 0.000468 AC: 14 AN: 29899

South Asian (SAS) AF: 0.0502 AC: 2469 AN: 49138

European-Finnish (FIN) AF: 0.170 AC: 6814 AN: 40072

Middle Eastern (MID) AF: 0.249 AC: 969 AN: 3884

European-Non Finnish (NFE) AF: 0.220 AC: 169758 AN: 772660

Other (OTH) AF: 0.187 AC: 8011 AN: 42923

GnomAD4 genome AF: 0.149 AC: 16389 AN: 110299 Hom.: 1374 Cov.: 22 AF XY: 0.126 AC XY: 4103 AN XY: 32589

African (AFR) AF: 0.0353 AC: 1083 AN: 30639

American (AMR) AF: 0.127 AC: 1302 AN: 10256

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 686 AN: 2610

East Asian (EAS) AF: 0.000558 AC: 2 AN: 3586

South Asian (SAS) AF: 0.0334 AC: 88 AN: 2631

European-Finnish (FIN) AF: 0.130 AC: 742 AN: 5688

Middle Eastern (MID) AF: 0.255 AC: 54 AN: 212

European-Non Finnish (NFE) AF: 0.227 AC: 11927 AN: 52517

Other (OTH) AF: 0.166 AC: 247 AN: 1489

Alfa AF: 0.138 Hom.: 1097

Bravo AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Feb 21, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 14, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ornithine carbamoyltransferase deficiency Benign:4

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Nov 24, 2014

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.83
PhyloP100		-0.10
BranchPoint Hunter		3.0
Mutation Taster		=36/64	disease causing (long InDel)

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

Other links and lift over

dbSNP: rs73196229; hg19: chrX-38240587;