X-38411953-G-C

Position:

• chrX-38411953-G-C

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.959G>C​(p.Arg320Pro) variant causes a missense change involving the alteration of a non-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. R320Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC ENST00000039007.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.583

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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-38411953-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97372.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant X-38411953-G-C is Pathogenic according to our data. Variant chrX-38411953-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 935343.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.959G>C	p.Arg320Pro	missense_variant	9/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.959G>C	p.Arg320Pro	missense_variant	11/12		NP_001394021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.959G>C	p.Arg320Pro	missense_variant	9/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-254168G>C		intron_variant		5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*709G>C		non_coding_transcript_exon_variant	10/11			ENSP00000496606.1
OTC	ENST00000643344.1	n.*709G>C		3_prime_UTR_variant	10/11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research	-	indicating that the boy is a Ornithine carbamoyltransferase deficiency patient. Parents and the boy underwent OTC gene testing simultaneously, and the results showed that the proband carried a hemizygous variant c.959G>C (Arg320Leu) in OTC gene, while the mother carried two compound heterozygous variants c.959G>C (Arg320Leu) and c.634G>A (Gly212Arg) in OTC gene . -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2019	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg320 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 1671317), which suggests that this may be a clinically significant amino acid residue. This variant has been observed to be de novo in an individual affected with OTC-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 320 of the OTC protein (p.Arg320Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Benign	0.18	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.75		Gain of catalytic residue at P319 (P = 0.0133);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		0.28
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs72558474; hg19: chrX-38271206; COSMIC: COSV105008509;