chrX-38367367-G-A

Position:

• chrX-38367367-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000039007.5(OTC):​c.154G>A​(p.Glu52Lys) 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. E52G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC ENST00000039007.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.96

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 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in ENST00000039007.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38367369-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97121.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-38367367-G-A is Pathogenic according to our data. Variant chrX-38367367-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.154G>A	p.Glu52Lys	missense_variant	2/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.154G>A	p.Glu52Lys	missense_variant	4/12		NP_001394021.1
OTC	XM_017029556.2	c.154G>A	p.Glu52Lys	missense_variant	2/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.154G>A	p.Glu52Lys	missense_variant	2/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1	n.246G>A		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1	c.154G>A	p.Glu52Lys	missense_variant, NMD_transcript_variant	2/11			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2018

This sequence change replaces glutamic acid with lysine at codon 52 of the OTC protein (p.Glu52Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ornithine transcarbamylase (OTC) deficiency (PMID: 10946359, 25433810, 17334707), being de novo in one of them (Invitae). ClinVar contains an entry for this variant (Variation ID: 97118). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Glu52Lys and p.Glu52Asp) in affected individuals suggests that this may be a clinically significant residue (PMID: 10946359, 25433810, 17334707). For these reasons, this variant has been classified as Pathogenic. -

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	0.85
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Gain of MoRF binding (P = 0.0134);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.98
gMVP		1.0

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: rs66521141; hg19: chrX-38226620;