rs66550389

chrX-38369854-G-AchrX-38369854-G-CchrX-38369854-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):c.275G>A(p.Arg92Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38369853-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 97150.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-38369854-G-A is Pathogenic according to our data. Variant chrX-38369854-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38369854-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.275G>A	p.Arg92Gln	missense_variant	3/10	ENST00000039007.5
OTC	NM_001407092.1	c.275G>A	p.Arg92Gln	missense_variant	5/12
OTC	XM_017029556.2	c.275G>A	p.Arg92Gln	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.275G>A	p.Arg92Gln	missense_variant	3/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.275G>A	p.Arg92Gln	missense_variant, NMD_transcript_variant	3/11
OTC	ENST00000488812.1	n.353+14G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 10, 2020	This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 1671317, 26753873, 30285816). It is absent from the gnomAD population database and thus is presumed to be rare. The c.275G>A (p.Arg92Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.275G>A (p.Arg92Gln) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the OTC protein (p.Arg92Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 1671317, 19138872, 26753873, 30285816). ClinVar contains an entry for this variant (Variation ID: 97152). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2022	- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		Gain of ubiquitination at K88 (P = 0.0337);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs66550389; hg19: chrX-38229107; COSMIC: COSV50000649;