X-38401313-T-G

Position:

• chrX-38401313-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000531.6(OTC):​c.425T>G​(p.Val142Gly) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.425T>G	p.Val142Gly	missense_variant	5/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.425T>G	p.Val142Gly	missense_variant	7/12		NP_001394021.1
OTC	XM_017029556.2	c.425T>G	p.Val142Gly	missense_variant	5/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.425T>G	p.Val142Gly	missense_variant	5/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-264808T>G		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000552 AC: 6 AN: 1087405 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 353621

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000744

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Val142 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 11793468), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with OTC deficiency (PMID: Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces valine with glycine at codon 142 of the OTC protein (p.Val142Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.95	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.73		Loss of stability (P = 8e-04);
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.98
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: rs72556261; hg19: chrX-38260566;