rs1800321

Variant names:

• chrX-38367350-A-G
• rs1800321
• NM_000531.6:c.137A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000531.6(OTC):​c.137A>G​(p.Lys46Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,200,554 control chromosomes in the GnomAD database, including 22,608 homozygotes. There are 82,733 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (3139 hom., 7685 hem., cov: 22)
  • Exomes 𝑓: 0.22 (19469 hom. 75048 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.43
• Publications: 31 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 -17 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000531.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014624894).
• BP6: Variant X-38367350-A-G is Benign according to our data. Variant chrX-38367350-A-G is described in ClinVar as Benign. ClinVar VariationId is 10994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.137A>G	p.Lys46Arg	missense_variant	Exon 2 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.137A>G	p.Lys46Arg	missense_variant	Exon 4 of 12		NP_001394021.1
OTC	XM_017029556.2	c.137A>G	p.Lys46Arg	missense_variant	Exon 2 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.137A>G	p.Lys46Arg	missense_variant	Exon 2 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-298771A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 28313 AN: 110592 Hom.: 3140 Cov.: 22

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.000836

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.302

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.187 AC: 34116 AN: 182760 AF XY: 0.180

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.000433

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.217 AC: 236649 AN: 1089911 Hom.: 19469 Cov.: 28 AF XY: 0.211 AC XY: 75048 AN XY: 356279

African (AFR) AF: 0.387 AC: 10145 AN: 26232

American (AMR) AF: 0.123 AC: 4316 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 5675 AN: 19323

East Asian (EAS) AF: 0.000497 AC: 15 AN: 30169

South Asian (SAS) AF: 0.0545 AC: 2940 AN: 53963

European-Finnish (FIN) AF: 0.173 AC: 6992 AN: 40503

Middle Eastern (MID) AF: 0.280 AC: 1155 AN: 4119

European-Non Finnish (NFE) AF: 0.234 AC: 195270 AN: 834588

Other (OTH) AF: 0.221 AC: 10141 AN: 45830

GnomAD4 genome AF: 0.256 AC: 28342 AN: 110643 Hom.: 3139 Cov.: 22 AF XY: 0.234 AC XY: 7685 AN XY: 32899

African (AFR) AF: 0.376 AC: 11398 AN: 30277

American (AMR) AF: 0.183 AC: 1897 AN: 10378

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 760 AN: 2632

East Asian (EAS) AF: 0.000838 AC: 3 AN: 3578

South Asian (SAS) AF: 0.0378 AC: 100 AN: 2649

European-Finnish (FIN) AF: 0.147 AC: 867 AN: 5878

Middle Eastern (MID) AF: 0.302 AC: 65 AN: 215

European-Non Finnish (NFE) AF: 0.239 AC: 12621 AN: 52839

Other (OTH) AF: 0.242 AC: 368 AN: 1519

Alfa AF: 0.245 Hom.: 30341

Bravo AF: 0.265

TwinsUK AF: 0.234 AC: 869

ALSPAC AF: 0.242 AC: 698

ESP6500AA AF: 0.376 AC: 1443

ESP6500EA AF: 0.241 AC: 1623

ExAC AF: 0.191 AC: 23146

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 05, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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.137A>G (p.Lys46Arg) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.19 in 199288 control chromosomes, at a frequency of 0.23 within the Non-Finnish European subpopulation (including 1588 homozygotes) and at a frequency of 0.39 within African subpopulation (including 943 homozygotes) in the gnomAD database,. The observed variant frequency within Non-Finnish European/African control individuals in the gnomAD database is approximately 50 and 85 fold respectively 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 a benign polymorphism found primarily in populations of Non-Finnish European/African origin. The variant, c.137A>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency without strong evidence of causality (Engel_2008, Zhong_2013, Dobrowolski_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Ornithine carbamoyltransferase deficiency Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30612563, 28324312) -

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. -

ORNITHINE TRANSCARBAMYLASE POLYMORPHISM Benign:1

Aug 01, 1989

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.41
Sift	Benign	0.26	T
Sift4G	Benign	0.44	T
Polyphen		0.18	B
Vest4		0.14
MPC		0.39
ClinPred		0.043	T
GERP RS		4.2
Varity_R		0.31
gMVP		0.84
Mutation Taster		=92/8	polymorphism (auto)

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

dbSNP: rs1800321; hg19: chrX-38226603; COSMIC: COSV50000046;