rs145777402

chrX-38401317-T-AchrX-38401317-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000531.6(OTC):c.429T>A(p.Tyr143Ter) variant causes a stop gained change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. Y143Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.520

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38401317-T-A is Pathogenic according to our data. Variant chrX-38401317-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1072591.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.429T>A	p.Tyr143Ter	stop_gained	5/10	ENST00000039007.5
OTC	NM_001407092.1	c.429T>A	p.Tyr143Ter	stop_gained	7/12
OTC	XM_017029556.2	c.429T>A	p.Tyr143Ter	stop_gained	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.429T>A	p.Tyr143Ter	stop_gained	5/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.466T>A		non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*179T>A		3_prime_UTR_variant, NMD_transcript_variant	6/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2020

This sequence change creates a premature translational stop signal (p.Tyr143*) in the OTC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with ornithine transcarbamylase deficiency (PMID: 23551631). Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	35
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A
Vest4		0.94
GERP RS		-0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38260570;