rs72554308

chrX-38367332-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):c.119G>A(p.Arg40His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.09

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 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000531.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38367331-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-38367332-G-A is Pathogenic according to our data. Variant chrX-38367332-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38367332-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.119G>A	p.Arg40His	missense_variant	2/10	ENST00000039007.5
OTC	NM_001407092.1	c.119G>A	p.Arg40His	missense_variant	4/12
OTC	XM_017029556.2	c.119G>A	p.Arg40His	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.119G>A	p.Arg40His	missense_variant	2/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.211G>A		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1	c.119G>A	p.Arg40His	missense_variant, NMD_transcript_variant	2/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087008 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 7951259, 19893582, 25026867). ClinVar contains an entry for this variant (Variation ID: 11014). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects OTC function (PMID: 11102556). This variant disrupts the p.Arg40 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7860066, 7951259, 19893582, 23209112, 25026867; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a heterozygous female became symptomatic with hyperammenomia and acute decompensation at 13 years of age [PMID 21070677]. Additionally, a family with a hemizygous male and heterozygous sister also became symptomatic in their teenage years [PMID 2095337]. Their mother, also heterozygous, was asymptomatic but showed small orotic aciduria after protein loading. This variant has also been observed in our internal database in a 10 y/o patient with recent symptoms of OTC deficiency. Another change at the same amino acid location (p.Arg40Cys) has been reported but is considered a variant of unknown significance by our classification criteria at this time. This variant is not conserved in all mammals. Computer based prediction softwares yield discordant results regarding the pathogenicity of this change. This variant has not been observed in the ExAC database but has been detected in multiple patients and it is thus classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 03, 2023	PS4, PP3, PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	Reported previously in association with a milder, later-onset ornithine transcarbamylase (OTC) deficiency phenotype in males as well as a late-onset, mild phenotype in heterozygous females (Pinner et al. 2010; Cavicchi et al. 2014); Reported to be associated with 26-35% residual OTC enzyme activity when expressed in CHO cells (Augustin et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9175746, 17334707, 32995020, 32934962, 9048915, 25026867, 7951259, 11768581, 11260212, 8863155, 30449781, 28324312, 31447099, 11102556, 21070677, 33272297) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 07, 2022	PP1, PP4, PM2, PM5, PS3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.99	A
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.022	D
Polyphen		0.54	P
Vest4		0.77
MutPred		0.98		Loss of MoRF binding (P = 0.0407);
MVP		0.91
MPC		0.61
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.94

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: rs72554308; hg19: chrX-38226585;