rs1057515879

Positions:

• chrX-38352772-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000531.6(OTC):​c.76C>T​(p.Arg26Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,187,958 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 9 hem.)
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 0.0002767
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 B:2
• Conservation: PhyloP100: -0.146

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a mutagenesis_site Loss of cleavage of the transit peptide and loss of localization to mitochondrial matrix; when associated with G-15 and G-23. (size 0) in uniprot entity OTC_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.1821695).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.76C>T	p.Arg26Trp	missense_variant, splice_region_variant	1/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.76C>T	p.Arg26Trp	missense_variant, splice_region_variant	3/12		NP_001394021.1
OTC	XM_017029556.2	c.76C>T	p.Arg26Trp	missense_variant, splice_region_variant	1/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.76C>T	p.Arg26Trp	missense_variant, splice_region_variant	1/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1	n.168C>T		splice_region_variant, non_coding_transcript_exon_variant	1/6	5
OTC	ENST00000643344.1	c.76C>T	p.Arg26Trp	missense_variant, splice_region_variant, NMD_transcript_variant	1/11			ENSP00000496606

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112081 Hom.: 0 Cov.: 23 AF XY: 0.0000584 AC XY: 2 AN XY: 34261

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 28 AN: 1075824 Hom.: 0 Cov.: 26 AF XY: 0.0000263 AC XY: 9 AN XY: 342776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000882

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112134 Hom.: 0 Cov.: 23 AF XY: 0.0000583 AC XY: 2 AN XY: 34324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the OTC protein (p.Arg26Trp). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with a positive newborn screening result for OTC-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 368257). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2016	Variant summary: The OTC c.76C>T (p.Arg26Trp) variant involves the alteration of a non-conserved nucleotide. This variant is located within the carbamoyl-P binding domain. 3/5 in silico tools predict a benign outcome for this variant, however this particular alteration has yet to be functionally assessed. . This variant is absent from control population dataset of ExAC. The variant was identified in a pt undergoing WES due to clinical presentations nonspecific and unrelated to ornithine transcabamylase deficiency, although, pt did report episodes of memory loss. The variant was inherited from reportedly unaffected father. Another alteration of the same codon, p.R26Q has been reported in several affected individuals with biochemically confirmed OTC-deficiency. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, but was cited as VUS by a reputable database/clinical diagnostic laboratory. The p.R26W may represent either a late-onset mild mutation or rare functional variant. At this point, there is no sufficient evidence to classify c.76C>T with confidence. Taken together, this variant is classified as VUS. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.000044	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.42	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.81	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.37
Sift	Benign	0.086	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.47
MPC		0.39
ClinPred		0.18	T
GERP RS		-0.071
Varity_R		0.085
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.052
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: rs1057515879; hg19: chrX-38212025; COSMIC: COSV50000849;