X-38411953-G-C

Variant names:

• chrX-38411953-G-C
• rs72558474
• NM_000531.6:c.959G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000531.6(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 NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.583
• Publications: 6 publications found

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-38411953-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 97372.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• 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 VariationId is 935343.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.959G>C	p.Arg320Pro	missense_variant	Exon 9 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.959G>C	p.Arg320Pro	missense_variant	Exon 11 of 12		NP_001394021.1
OTC	XM_017029556.2	c.*92G>C		downstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.959G>C	p.Arg320Pro	missense_variant	Exon 9 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-254168G>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

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

Jul 15, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with OTC-related conditions (Invitae).

Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 .

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
PhyloP100		0.58
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Vest4		0.82
ClinPred		0.99	D
GERP RS		0.28
Varity_R		0.98
gMVP		0.98
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72558474; hg19: chrX-38271206; COSMIC: COSV105008509;