chrX-38401310-G-A

Position:

• chrX-38401310-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.422G>A​(p.Arg141Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.54

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity OTC_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-38401310-G-A is Pathogenic according to our data. Variant chrX-38401310-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38401310-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.422G>A	p.Arg141Gln	missense_variant	5/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.422G>A	p.Arg141Gln	missense_variant	7/12		NP_001394021.1
OTC	XM_017029556.2	c.422G>A	p.Arg141Gln	missense_variant	5/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.422G>A	p.Arg141Gln	missense_variant	5/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-264811G>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function. ClinVar contains an entry for this variant (Variation ID: 10987). This variant is also known as Arg109Gln. This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 3170748, 8830175, 8985493, 30175132). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the OTC protein (p.Arg141Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2024	Variant summary: OTC c.422G>A (p.Arg141Gln) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.422G>A has been reported in the literature as de novo or as maternally inherited in multiple hemizugous or heterozygous individuals affected with Ornithine Transcarbamylase Deficiency and in one family, one male and five heterozygous females are symptomatic while two other heterozygous females are asymptomatic (Madalena_1988, Ahrens_1996). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8985493, 3170748). ClinVar contains an entry for this variant (Variation ID: 10987). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	Published functional studies that R141Q is associated with significantly reduced OTC activity compared to wild-type (Lee et al., 1989; Augustin et al., 2000).; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33272297, 31589614, 28324312, 8985493, 8830175, 17044854, 1757964, 3170748, 1627356, 2556444, 11102556, 30175132) -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Gain of sheet (P = 0.1208);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.99

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: rs68026851; hg19: chrX-38260563; COSMIC: COSV50004515;