chrX-38403673-A-T

Variant names:

• chrX-38403673-A-T
• rs72558406
• NM_000531.6:c.596A>T

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.596A>T​(p.Asn199Ile) 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. N199D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.89
• Publications: 0 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 34 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-38403672-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 97264.Status of the report is no_assertion_criteria_provided, 0 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, 0.996
• PP5: Variant X-38403673-A-T is Pathogenic according to our data. Variant chrX-38403673-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2629679.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.596A>T	p.Asn199Ile	missense	Exon 6 of 10	NP_000522.3
	OTC	NM_001407092.1		c.596A>T	p.Asn199Ile	missense	Exon 8 of 12	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.596A>T	p.Asn199Ile	missense	Exon 6 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262448A>T		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.596A>T	p.Asn199Ile	missense	Exon 8 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

OTC-related disorder Pathogenic:1

Feb 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTC c.596A>T variant is predicted to result in the amino acid substitution p.Asn199Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different amino acid substitutions impacting the p.Asn199 amino acid have been reported in patients with OTC deficiency (e.g., p.Asn199His in Ali et al. 2018. PubMed ID: 30175132; p.Asn199Asp in Yamaguchi et al. 2006. PubMed ID: 16786505; p.Asn199Ser in Tuchman et al. 2002. PubMed ID: 11793468). Numerous other amino acid substitutions surrounding this location have also been reported in patients with OTC deficiency (Human Gene Mutation Database, https://www.hgmd.cf.ac.uk/). Taken together, the c.596A>T (p.Asn199Ile) variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of catalytic residue at D196 (P = 0.2456)
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		1.0
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs72558406; hg19: chrX-38262926;