rs72558413

Positions:

• chrX-38403695-G-A
• chrX-38403695-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.618G>A​(p.Met206Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,096,986 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.57

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.

• PS1: Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38403695-G-A is Pathogenic according to our data. Variant chrX-38403695-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1297045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.618G>A	p.Met206Ile	missense_variant	6/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.618G>A	p.Met206Ile	missense_variant	8/12		NP_001394021.1
OTC	XM_017029556.2	c.618G>A	p.Met206Ile	missense_variant	6/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.618G>A	p.Met206Ile	missense_variant	6/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262426G>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183114 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67680

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096986 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362372

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 21, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase deficiency (MIM#311250). (I) 0108 - This gene is associated with X-linked disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In males, the phenotypic spectrum can range from lethal neonatal onset to milder forms in late childhood or adulthood while in heterozygous females, the phenotypic spectrum can range from asymptomatic to having recurrent hyperammonemia and/or neurologic impairment depending on the pattern of X-chromosome inactivation in the liver (OMIM, GeneReviews). In addition, individuals with pathogenic variants associated with mild, late-onset disease may experience severe hyperammonemia depending on exposure to strong environmental stressors (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated OTCace domain. (I) 0705 - No comparable variants have previous evidence for pathogenicity. Changes to lysine and arginine have been regarded as pathogenic and reported in individuals with ornithine transcarbamylase deficiency (ClinVar). However, these changes are not regarded as comparable because they have a higher Grantham score and may have a more deleterious effect. (I) 0803 - This variant has limited previous evidence of pathogenicity. It has been regarded as pathogenic in ClinVar by a diagnostic laboratory. In addition, a different nucleotide substitution resulting in the same amino acid change was detected in a heterozygous baby girl with ornithine transcarbamylase deficiency (PMID: 11793483). Authors suggest mother does not have the variant considering allopurinol test; however, genetic studies were not performed to confirm this result (PMID: 11793483). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Biopsy of patient’s intestinal mucosa has shown only 5% of OTC activity (PMID: 11793483). In addition, yeast complementation assay performed in S. cerevisiae has shown that this variant resulted in decreased yeast growth compared to wild-type (PMID: 37146589). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 19, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	-0.12	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.59
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.069	B
Vest4		0.45
MutPred		0.86		Gain of catalytic residue at M206 (P = 0.0428);
MVP		0.99
MPC		0.46
ClinPred		0.16	T
GERP RS		5.9
Varity_R		0.71
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72558413; hg19: chrX-38262948; COSMIC: COSV50001850; COSMIC: COSV50001850;