rs72554356

Positions:

• chrX-38381417-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 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 (★★). 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:8
• Conservation: PhyloP100: -0.465

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000531.6
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.374C>T	p.Thr125Met	missense_variant	4/10	ENST00000039007.5
OTC	NM_001407092.1	c.374C>T	p.Thr125Met	missense_variant	6/12
OTC	XM_017029556.2	c.374C>T	p.Thr125Met	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.374C>T	p.Thr125Met	missense_variant	4/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.411C>T		non_coding_transcript_exon_variant	4/6	5
OTC	ENST00000643344.1	c.*124C>T		3_prime_UTR_variant, NMD_transcript_variant	5/11

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111307 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33531

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: 2 AN: 182605 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67159

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: 17 AN: 1063696 Hom.: 0 Cov.: 26 AF XY: 0.0000331 AC XY: 11 AN XY: 332178

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: 1 AN: 111360 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33594

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: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

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	Genome-Nilou Lab	Nov 07, 2021	- -
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	Invitae	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:1 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	0.62
DANN	Benign	0.92
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.69	P
Vest4		0.76
MVP		0.99
MPC		0.40
ClinPred		0.027	T
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

Other links and lift over

dbSNP: rs72554356; hg19: chrX-38240670;