rs67486158

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The ENST00000039007.5(OTC):c.148G>A(p.Gly50Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,197,395 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G50A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 8 hem. )

Consequence

OTC
ENST00000039007.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 3.70

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000039007.5

BP4

Computational evidence support a benign effect (MetaRNN=0.24352771).

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OTC	NM_000531.6 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	2/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	4/12		NP_001394021.1
OTC	XM_017029556.2 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	2/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
OTC	ENST00000039007.5 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	2/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000488812.1 linkuse as main transcript	n.240G>A		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant, NMD_transcript_variant	2/11			ENSP00000496606

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111170

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33376

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:

0.000281

Gnomad SAS

AF:

0.000376

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000491

AC:

AN:

183116

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

67764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000612

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000249

AC:

AN:

1086172

Hom.:

Cov.:

AF XY:

0.0000227

AC XY:

AN XY:

352170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000518

Gnomad4 EAS exome

AF:

0.000299

Gnomad4 SAS exome

AF:

0.0000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000656

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111223

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33439

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000316

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 09, 2019	- -

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

-0.76

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.56

Sift

Benign

0.24

Sift4G

Benign

0.39

Polyphen

0.96

Vest4

0.20

MutPred

0.77

Loss of ubiquitination at K46 (P = 0.0429);

MVP

0.97

MPC

0.74

ClinPred

0.094

GERP RS

5.4

Varity_R

0.66

gMVP

0.99

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