rs1800321

Positions:

• chrX-38367350-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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:15
• Conservation: PhyloP100: 7.43

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000531.6
• 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 id is 10994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38367350-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
OTC	NM_000531.6	c.137A>G	p.Lys46Arg	missense_variant	2/10	ENST00000039007.5
OTC	NM_001407092.1	c.137A>G	p.Lys46Arg	missense_variant	4/12
OTC	XM_017029556.2	c.137A>G	p.Lys46Arg	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.137A>G	p.Lys46Arg	missense_variant	2/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.229A>G		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1	c.137A>G	p.Lys46Arg	missense_variant, NMD_transcript_variant	2/11

Frequencies

GnomAD3 genomes AF: 0.256 AC: 28313 AN: 110592 Hom.: 3140 Cov.: 22 AF XY: 0.233 AC XY: 7652 AN XY: 32838

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

GnomAD3 exomes AF: 0.187 AC: 34116 AN: 182760 Hom.: 2756 AF XY: 0.180 AC XY: 12127 AN XY: 67384

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 SAS exome AF: 0.0502

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

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.000497

Gnomad4 SAS exome AF: 0.0545

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.221

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

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.000838

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.242

Alfa AF: 0.236 Hom.: 22717

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
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	PreventionGenetics, part of Exact Sciences	Feb 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Ornithine carbamoyltransferase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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	Invitae	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

clinical testing

GeneDx

Mar 03, 2015

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

ORNITHINE TRANSCARBAMYLASE POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 01, 1989

- -

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
MutationTaster	Benign	0.064	P
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

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

LitVar

Other links and lift over

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