rs72556260

Positions:

• chrX-38401306-G-C

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.418G>C​(p.Ala140Pro) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.54

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 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, 0.996
• PP5: Variant X-38401306-G-C is Pathogenic according to our data. Variant chrX-38401306-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97196.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.418G>C	p.Ala140Pro	missense_variant	5/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.418G>C	p.Ala140Pro	missense_variant	7/12		NP_001394021.1
OTC	XM_017029556.2	c.418G>C	p.Ala140Pro	missense_variant	5/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.418G>C	p.Ala140Pro	missense_variant	5/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1	n.455G>C		non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*168G>C		3_prime_UTR_variant, NMD_transcript_variant	6/11			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 15, 2016

Variant summary: The OTC c.418G>C (p.Ala140Pro) variant involves the alteration of a conserved nucleotide and results in a replacement of a small size and hydrophobic Alanine (A) with a medium size and hydrophobic Proline (P) in the Carbamoyl phosphate binding domain of the OTC enzyme (ACMG-PM1). 5/5 in silico tools predict a damaging outcome for this substitution (ACMG-PP3). This variant is absent form the general population (ExAC) (ACMG-PM2) while it was reported in at-least 3 biochemically and clinically well characterized neonatal onset OTC deficiency patients indicating causality. In addition, at-least one clinical diagnostic laboratory has classified this variant as pathogenic (ACMG-PP5). However, the effect of this variant on functional OTC enzyme deficiency has not been reported. Taken together, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.087	T
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of stability (P = 0.0812);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		1.0
gMVP		0.99

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: rs72556260; hg19: chrX-38260559;