rs72556271

chrX-38401370-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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:4
• Conservation: PhyloP100: 8.89

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 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 id is 97215.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 id is 97216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.482A>G	p.Asn161Ser	missense_variant	5/10	ENST00000039007.5
OTC	NM_001407092.1	c.482A>G	p.Asn161Ser	missense_variant	7/12
OTC	XM_017029556.2	c.482A>G	p.Asn161Ser	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.482A>G	p.Asn161Ser	missense_variant	5/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.519A>G		non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*232A>G		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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 09, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OTC function (PMID: 17041896). 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. ClinVar contains an entry for this variant (Variation ID: 97216). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8786061, 11388595, 12083811, 21956151, 25994866). This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2015	The N161S missense variant in the OTC gene has been reported previously in associationwith OTC deficiency (Tuchman and Plante, 1995; Lipskind et al. 2011). Approximately20% of females who are heterozygous for variants in the OTC gene are clinicallysymptomatic with disease severity similar to males with partial deficiency (Yamaguchi etal., 2006; Tuchman et al., 2002). Therefore, we interpret the N161S variant as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -

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
MutationTaster	Benign	1.0	D
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

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: rs72556271; hg19: chrX-38260623;