X-38421078-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_000531.6(OTC):c.1061T>G(p.Phe354Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000423 in 1,181,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 6.65

Variant links:

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 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant X-38421078-T-G is Pathogenic according to our data. Variant chrX-38421078-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97104.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 10 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 12 of 12		NP_001394021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTC	ENST00000039007.5 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 10 of 10	1	NM_000531.6	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1 link	c.172-245043T>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1	B4E171
OTC	ENST00000643344.1 link	n.*811T>G		downstream_gene_variant				ENSP00000496606.1	A0A2R8Y829

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111431

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182812

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000374

AC:

AN:

1069717

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

337543

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

25886

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35164

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19186

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30083

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

53475

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40393

Gnomad4 NFE exome

AF:

0.00000490

AC:

AN:

816287

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

45177

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111431

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33633

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000189

AC:

0.0000188551

AN:

0.0000188551

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:5Uncertain:1

Aug 03, 2017

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 13-year old boy diagnosed with late-onset ornithine transcarbamylase deficiency based on hyperammonemia and 1.8% residual OTC enzyme activity detected in his liver tissue frozen at autopsy (PMID: 8857803). This variant has been observed in a male with first presentation of hyperammonemia at age 14, as well as in his 55-year old, asymptomatic grandfather (PMID: 10946359). OTC enzyme activity was not determined in the proband. This variant has also been observed in a newborn girl diagnosed with phenylketonuria and unaffected with symptoms of ornithine transcarbamylase deficiency (PMID: 32853555). Her grandfather and younger male sibling were unaffected carriers of this variant. This variant has been identified in 1/182812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein (p.Phe354Cys). This variant is present in population databases (rs72558495, gnomAD 0.001%). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 9266388, 10869432). ClinVar contains an entry for this variant (Variation ID: 97104). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt OTC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Nov 15, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182812 control chromosomes. c.1061T>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 2% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The OTC c.1061T>G (p.F354C) variant was previously reported in mild ornithine transcarbamylase deficiency (PMID: 8857803; 16786505). -

not provided

Pathogenic:2

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 04, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9266388, 8857803, 28324312, 16786505, 32853555, 37146589, 11793468, 10869432, 10946359) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.60

MutPred

0.70

Loss of ubiquitination at K353 (P = 0.0709);

MVP

1.0

MPC

1.4

ClinPred

0.85

GERP RS

5.2

Varity_R

0.63

gMVP

0.96

Mutation Taster

=78/22

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over