NM_000531.6:c.482A>G

Variant names:

• chrX-38401370-A-G
• rs72556271
• NM_000531.6:c.482A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.482A>G​(p.Asn161Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N161D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.89
• Publications: 11 publications found

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38401369-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 97215.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-38401370-A-G is Pathogenic according to our data. Variant chrX-38401370-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 97216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.482A>G	p.Asn161Ser	missense_variant	Exon 5 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.482A>G	p.Asn161Ser	missense_variant	Exon 7 of 12		NP_001394021.1
OTC	XM_017029556.2	c.482A>G	p.Asn161Ser	missense_variant	Exon 5 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.482A>G	p.Asn161Ser	missense_variant	Exon 5 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-264751A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:3

Apr 26, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, NM_000531.5(OTC):c.482A>G (p.Asn161Ser), is classified as pathogenic based on multiple lines of evidence. It is a nonsynonymous substitution in exon 5 of the OTC gene, which is associated with X-linked ornithine transcarbamylase deficiency, a urea cycle disorder. The variant is absent from major population databases including gnomAD, ESP, and 1000 Genomes, supporting PM2. In silico tools predict a damaging effect on the protein: PolyPhen-2 scores it as probably damaging (0.998), MutationTaster predicts it as deleterious (score = 1), and REVEL assigns a high score of 0.87. The affected residue is highly conserved (GERP score: 5.97), and the change occurs at a site where other pathogenic variants have been reported, fulfilling PM5. Functional studies cited in the literature (PMID: 17041896) demonstrate a deleterious impact on enzyme function, supporting PS3. Furthermore, the variant is reported as pathogenic in ClinVar,and was not detected in either parent, indicating a likely de novo event (PS2 or PM6 if confirmed). Based on ACMG/AMP guidelines, the variant meets criteria PM2, PS3, PM5, PM3, PP3, PP5, and PP2, supporting its classification as pathogenic. -

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 161 of the OTC protein (p.Asn161Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8786061, 11388595, 12083811, 21956151, 25994866). ClinVar contains an entry for this variant (Variation ID: 97216). Experimental studies have shown that this missense change affects OTC function (PMID: 17041896). For these reasons, this variant has been classified as Pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: expression studies demonstrate no residual OTC enzyme activity compared to wildtype (Kim et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7627182, 21956151, 11388595, 19138872, 12754713, 25994866, 17334707, 12083811, 11117428, 30223008, 28324312, 32034732, 33272297, 32778825, 37146589, 32447331, 32922350, 27915290, 17041896, 28266016) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		Gain of phosphorylation at S156 (P = 0.1047);
MVP		0.94
MPC		0.38
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.98
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72556271; hg19: chrX-38260623;