X-38403681-C-T

Position:

• chrX-38403681-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000531.6(OTC):​c.604C>T​(p.His202Tyr) variant causes a missense change. 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. H202P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.63

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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-38403681-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 949644.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-38403681-C-T is Pathogenic according to our data. Variant chrX-38403681-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97267.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.604C>T	p.His202Tyr	missense_variant	6/10	ENST00000039007.5
OTC	NM_001407092.1	c.604C>T	p.His202Tyr	missense_variant	8/12
OTC	XM_017029556.2	c.604C>T	p.His202Tyr	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.604C>T	p.His202Tyr	missense_variant	6/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*354C>T		3_prime_UTR_variant, NMD_transcript_variant	7/11
OTC	ENST00000488812.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Oct 15, 2019

This variant has been previously reported as a hemizygous change in patients with Ornithine Transcarbamylase Deficiency (OTC deficiency) (PMID: 9266388, 30285816). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.604C>T (p.His202Tyr) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Additional amino acid changes at the same codon have been reported in affected individuals with OTC deficiency (PMID: 9501271, 25433810). Based on the available evidence, the c.604C>T (p.His202Tyr) variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.89
Sift	Benign	0.14	T
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.89		Loss of catalytic residue at L201 (P = 0.1858);
MVP		0.98
MPC		1.3
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558408; hg19: chrX-38262934;