rs72554356

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

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 (★★).

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

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.374C>T	p.Thr125Met	missense_variant	Exon 4 of 10	ENST00000039007.5	NP_000522.3	P00480
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		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-284704C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111307

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33531

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

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182605

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

67159

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.0000375

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111360

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33594

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	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) -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 28, 2023

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

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

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

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

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

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