Genetic Variant NM_000531.6:c.236G>A (chrX-38369815-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000531.6(OTC):c.236G>A(p.Gly79Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.81

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_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant X-38369815-G-A is Pathogenic according to our data. Variant chrX-38369815-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.236G>A	p.Gly79Glu	missense_variant	Exon 5 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTC	ENST00000039007.5 link	c.236G>A	p.Gly79Glu	missense_variant	Exon 3 of 10	1	NM_000531.6	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1 link	c.172-296306G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1	B4E171
OTC	ENST00000488812.1 link	n.328G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5
OTC	ENST00000643344.1 link	n.236G>A		non_coding_transcript_exon_variant	Exon 3 of 11			ENSP00000496606.1	A0A2R8Y829

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1080274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

348298

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:2

Jan 31, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTC c.236G>A (p.Gly79Glu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domian (IPR006132) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182630 control chromosomes (gnomAD). c.236G>A has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency (Tuchman_1992, McCullough_2000). At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected OTC protein function (Tuchman_2002). The following publications have been ascertained in the context of this evaluation (PMID: 36303552, 37146589, 28324312, 10946359, 11793468, 1480464, 16786505). ClinVar contains an entry for this variant (Variation ID: 11006). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.79

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.95

MutPred

0.91

Gain of solvent accessibility (P = 0.0171);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

6.0

Varity_R

0.98

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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