rs72554356

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_000531.6(OTC):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,175,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 11 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:8

Conservation

PhyloP100: -0.465

Publications

13 publications found

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 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

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000531.6

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.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
OTC	NM_000531.6 link	c.374C>T	p.Thr125Met	missense_variant	Exon 4 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1 link	c.374C>T	p.Thr125Met	missense_variant	Exon 6 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.374C>T	p.Thr125Met	missense_variant	Exon 4 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.374C>T	p.Thr125Met	missense_variant	Exon 4 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1 link	c.172-284704C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111307

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182605

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000723

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1063696

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

332178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25796

American (AMR)

AF:

0.0000285

AC:

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19150

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30079

South Asian (SAS)

AF:

0.0000375

AC:

AN:

53280

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40469

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4040

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

810751

Other (OTH)

AF:

0.0000667

AC:

AN:

44982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00000898

AC:

AN:

111360

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33594

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30609

American (AMR)

AF:

0.00

AC:

AN:

10447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53109

Other (OTH)

AF:

0.00

AC:

AN:

1513

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:4

Dec 10, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.374C>T (p.Thr125Met) in OTC has been submitted to ClinVar as a Variant of Uncertain Significance. This variant has been observed in an individual affected with OTC deficiency (Gilbert-Dussardier B et al). Experimental studies have shown that this missense change causes lack of OTC enzymatic activity in vitro (Suriano G et al) This p.Thr125Met variant has allele frequency of 0.001095% in the gnomAD and novel (not in any individuals) in 1000 genome database. The amino acid Thr at position 125 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the OTC protein (p.Thr125Met). This variant is present in population databases (rs72554356, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with OTC deficiency (PMID: 8807340). ClinVar contains an entry for this variant (Variation ID: 97175). 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 not expected to disrupt OTC protein function. Experimental studies have shown that this missense change affects OTC function (PMID: 17613537). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1Uncertain:2

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the T125M variant has reduced activity compared to wild type (Suriano et al., 2007); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with OTC deficiency by enzyme results, however full sequencing of OTC gene was not performed (Gilbert-Dussardier et al., 1996); This variant is associated with the following publications: (PMID: 17613537, 25637381, 27703146, 8807340, 28324312, 9452049) -

not specified

Uncertain:1

Jul 28, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTC c.374C>T (p.Thr125Met) results in a non-conservative amino acid change located in the carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 182605 control chromosomes, including 2 hemizygotes, suggesting the variant may be benign. c.374C>T has been reported in the literature as a hemizygous genotype in at least one individual affected with neonatal onset Ornithine Transcarbamylase Deficiency who also had two unaffected female relatives who carried the variant, however X-inactivation pattern was not reported in these individuals (e.g. Gilbert-Dussardier_1996, Gobin-Limballe_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in little to no enzyme activity compared to the WT protein (Suriano_2007). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 8807340, 34014569, 17613537). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hyperammonemia

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

0.62

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.68

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

1.3

PhyloP100

-0.47

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.67

REVEL

Uncertain

0.59

Sift

Benign

0.12

Sift4G

Benign

0.22

Polyphen

0.69

Vest4

0.76

MVP

0.99

MPC

0.40

ClinPred

0.027

GERP RS

-3.0

Varity_R

0.13

gMVP

0.68

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over