rs72554309

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000531.6(OTC):c.127C>A(p.Leu43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,200,139 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L43F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.97

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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6 linkuse as main transcript	c.127C>A	p.Leu43Ile	missense_variant	2/10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 linkuse as main transcript	c.127C>A	p.Leu43Ile	missense_variant	4/12		NP_001394021.1
OTC	XM_017029556.2 linkuse as main transcript	c.127C>A	p.Leu43Ile	missense_variant	2/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTC	ENST00000039007.5 linkuse as main transcript	c.127C>A	p.Leu43Ile	missense_variant	2/10	1	NM_000531.6	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-298781C>A		intron_variant		5		ENSP00000417050.1	B4E171
OTC	ENST00000488812.1 linkuse as main transcript	n.219C>A		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1 linkuse as main transcript	n.127C>A		non_coding_transcript_exon_variant	2/11			ENSP00000496606.1	A0A2R8Y829

Frequencies

GnomAD3 genomes

AF:

0.0000896

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33824

show subpopulations

Gnomad AFR

AF:

0.000326

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

GnomAD4 exome

AF:

0.00000919

AC:

AN:

1088473

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

354173

show subpopulations

Gnomad4 AFR exome

AF:

0.000343

Gnomad4 AMR exome

AF:

0.0000284

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

AF:

0.0000896

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33824

show subpopulations

Gnomad4 AFR

AF:

0.000326

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:

0.000102

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 23, 2022	This OTC variant (rs72554309) is rare (<0.1%) in a large population dataset (gnomAD: 2/21659 total alleles; 0.009%; 1 hemizygote –less than 30 years-old) and has been reported in ClinVar. A previously reported alternate pathogenic missense variant (p.Leu43Pro) occurs at this amino acid position. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated. The leucine residue at this position is strongly conserved across the vetrebrate species accessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.127C>A (p.Leu43Ile) to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 43 of the OTC protein (p.Leu43Ile). This variant is present in population databases (rs72554309, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with OTC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1348491). 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%. 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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 04, 2023

Variant summary: OTC c.127C>A (p.Leu43Ile) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183119 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.127C>A in individuals affected with Ornithine Transcarbamylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.71

Sift

Benign

0.14

Sift4G

Benign

0.097

Polyphen

0.96

Vest4

0.67

MVP

0.75

MPC

1.2

ClinPred

0.79

GERP RS

2.6

Varity_R

0.65

gMVP

0.92

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