X-38403681-C-T

Variant names:

• chrX-38403681-C-T
• rs72558408
• NM_000531.6:c.604C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 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 (★).

• 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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.604C>T	p.His202Tyr	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.604C>T	p.His202Tyr	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2	c.604C>T	p.His202Tyr	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.604C>T	p.His202Tyr	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262440C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

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

Oct 15, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
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;