dbSNP rs779154479: OTC:p.Leu103Phe (chrX-38381350-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_000531.6(OTC):c.307C>T(p.Leu103Phe) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

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

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Publications

0 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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000531.6

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.307C>T	p.Leu103Phe	missense	Exon 4 of 10	NP_000522.3
	OTC	NM_001407092.1		c.307C>T	p.Leu103Phe	missense	Exon 6 of 12	NP_001394021.1	P00480

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTC	ENST00000039007.5	TSL:1 MANE Select	c.307C>T	p.Leu103Phe	missense	Exon 4 of 10	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284771C>T		intron	N/A	ENSP00000417050.1	B4E171
OTC	ENST00000713758.1		c.307C>T	p.Leu103Phe	missense	Exon 6 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1072699

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342119

African (AFR)

AF:

0.00

AC:

AN:

25960

American (AMR)

AF:

0.00

AC:

AN:

34974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19182

East Asian (EAS)

AF:

0.00

AC:

AN:

30065

South Asian (SAS)

AF:

0.00

AC:

AN:

52955

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819817

Other (OTH)

AF:

0.00

AC:

AN:

45237

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ornithine carbamoyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

PhyloP100

1.7

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.80

Sift

Benign

0.26

Sift4G

Benign

0.70

Polyphen

1.0

Vest4

0.65

MutPred

0.54

Loss of stability (P = 0.1172)

MVP

0.90

MPC

1.2

ClinPred

0.96

GERP RS

4.9

Varity_R

0.87

gMVP

0.89

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over