rs72554324

Variant names:

• chrX-38367401-T-C
• rs72554324
• NM_000531.6:c.188T>C

Variant summary

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

The NM_000531.6(OTC):​c.188T>C​(p.Leu63Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.39

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, 0.996

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.188T>C	p.Leu63Pro	missense_variant	Exon 2 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.188T>C	p.Leu63Pro	missense_variant	Exon 4 of 12		NP_001394021.1
OTC	XM_017029556.2	c.188T>C	p.Leu63Pro	missense_variant	Exon 2 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.188T>C	p.Leu63Pro	missense_variant	Exon 2 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-298720T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000488812.1	n.280T>C		non_coding_transcript_exon_variant	Exon 2 of 6	5
OTC	ENST00000643344.1	n.188T>C		non_coding_transcript_exon_variant	Exon 2 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ornithine carbamoyltransferase deficiency Uncertain:1

Mar 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 63 of the OTC protein (p.Leu63Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 9143919). ClinVar contains an entry for this variant (Variation ID: 97129). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.98
Sift	Benign	0.055	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Gain of methylation at K64 (P = 0.0538);
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		5.4
Varity_R		1.0
gMVP		1.0

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: rs72554324; hg19: chrX-38226654;