X-38403695-G-T

Variant names:

• chrX-38403695-G-T
• rs72558413
• NM_000531.6:c.618G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP5

The NM_000531.6(OTC):​c.618G>T​(p.Met206Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M206K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.57
• 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 10 ACMG points.

• PS1: Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 29 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-38403694-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 968929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP5: Variant X-38403695-G-T is Pathogenic according to our data. Variant chrX-38403695-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2627014.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.618G>T	p.Met206Ile	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.618G>T	p.Met206Ile	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2	c.618G>T	p.Met206Ile	missense_variant	Exon 6 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.618G>T	p.Met206Ile	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262426G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2 -

not specified Uncertain:1

Apr 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTC c.618G>T (p.Met206Ile) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.618G>T in individuals affected with Ornithine Transcarbamylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Other variants affecting this residue has been reported in individuals affected with the disease c.617T>G (PMID: 10405441), c.618G>C (PMID 11793483) however, this information is not sufficient to associate this variant with the disease. ClinVar contains an entry for this variant (Variation ID: 2627014). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	-0.12	N
PhyloP100		4.6
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		0.60	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.88
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72558413; hg19: chrX-38262948;