rs67294955

Positions:

• chrX-38403660-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.583G>A​(p.Gly195Arg) 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. 12/20 in silico tools predict a damaging 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:4
• 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 strand (size 5) in uniprot entity OTC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-38403660-G-A is Pathogenic according to our data. Variant chrX-38403660-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.583G>A	p.Gly195Arg	missense_variant	6/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.583G>A	p.Gly195Arg	missense_variant	8/12		NP_001394021.1
OTC	XM_017029556.2	c.583G>A	p.Gly195Arg	missense_variant	6/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.583G>A	p.Gly195Arg	missense_variant	6/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262461G>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OTC function (PMID: 9609999). 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: 97255). This missense change has been observed in individual(s) with OTC deficiency (PMID: 7951259, 9609999, 25433810, 30175132). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 195 of the OTC protein (p.Gly195Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2024	Published functional studies demonstrate this variant is associated with approximately 2.5% residual enzyme activity (PMID: 9609999); Not observed in large population cohorts (gnomAD); 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: 8786061, 34014557, 9286441, 17041896, 17044854, 29623395, 19138872, 22728053, 8112735, 9609999, 28324312, 32934962, 32034732, 32778825, 37593415, 33272297, 30175132, 7951259, 37146589) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.99		Gain of MoRF binding (P = 0.0211);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs67294955; hg19: chrX-38262913; COSMIC: COSV50001107;