rs67486158

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000531.6(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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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
NM_000531.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.70

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

ornithine carbamoyltransferase deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000531.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.

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 rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 2 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 4 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 2 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 2 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-298760G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111170

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000491

AC:

AN:

183116

AF XY:

0.0000590

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 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

African (AFR)

AF:

0.00

AC:

AN:

26173

American (AMR)

AF:

0.00

AC:

AN:

35187

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19291

East Asian (EAS)

AF:

0.000299

AC:

AN:

30150

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40499

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

831172

Other (OTH)

AF:

0.0000656

AC:

AN:

45710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111223

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33439

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30583

American (AMR)

AF:

0.00

AC:

AN:

10436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.000282

AC:

AN:

3545

South Asian (SAS)

AF:

0.000377

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5901

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53051

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000228

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

Aug 09, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

3.7

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

Mutation Taster

=60/40

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over