X-38403703-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_000531.6(OTC):c.626C>G(p.Ala209Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,208,542 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 48 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 48 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.52

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

BS2

High Hemizygotes in GnomAdExome4 at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.626C>G	p.Ala209Gly	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.626C>G	p.Ala209Gly	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.626C>G	p.Ala209Gly	missense_variant	Exon 6 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.626C>G	p.Ala209Gly	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-262418C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000805

AC:

AN:

111796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33980

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

183102

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000858

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000125

AC:

137

AN:

1096746

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

362160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.0000805

AC:

AN:

111796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33980

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000169

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:4

Aug 30, 2024

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 alanine with glycine at codon 209 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 not been reported in individuals affected with ornithine carbamoyltransferase deficiency in the literature. This variant has been identified in 12/204945 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, p.Ala209Val, is known to be disease-causing (ClinVar variation ID: 97275), indicating that alanine at this position is important for protein function. Due to the lack of available clinical evidence, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 09, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 17, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 209 of the OTC protein (p.Ala209Gly). This variant is present in population databases (rs72558417, gnomAD 0.01%), 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: 426468). 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%. This variant disrupts the p.Ala209 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8530002, 8807340, 9286441, 10070627, 11793468, 12536032, 25433810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Uncertain:1

Apr 14, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A209G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, different amino acid substitutions at the same position (A209V and A209E) have been reported in individuals with biochemical findings consistent with OTC deficiency, supporting the functional importance of this region of the protein (Garcia-Perez et al., 1995; Bailly et al., 2015). The A209V variant was apparently de novo in a female with intellectual disability and episodes of coma, while A209E was identified in an adult female with rapidly progressive neuropsychological symptoms and coma (Garcia-Perez et al., 1995; Bailly et al., 2015). However, the A209G variant identified in this individual is observed in 6/47912 (0.013%) alleles from individuals of European background, including one hemizygous individual, in the ExAC dataset (Lek et al., 2016). The A209G variant is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether the A209G variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.84

Sift

Uncertain

0.014

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.73

MVP

0.95

MPC

1.1

ClinPred

0.53

GERP RS

5.9

Varity_R

0.88

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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