rs72556296

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000531.6(OTC):c.571C>G(p.Leu191Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,958 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L191F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

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: 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_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000531.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38403648-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97250.Status of the report is no_assertion_criteria_provided, 0 stars.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.571C>G	p.Leu191Val	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.571C>G	p.Leu191Val	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.571C>G	p.Leu191Val	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.571C>G	p.Leu191Val	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-262473C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26354

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30182

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54047

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839174

Other (OTH)

AF:

0.00

AC:

AN:

45990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37146589) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Uncertain

0.62

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

0.25

PhyloP100

1.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.020

REVEL

Uncertain

0.44

Sift

Benign

0.96

Sift4G

Benign

0.99

Polyphen

0.010

Vest4

0.46

MutPred

0.54

Loss of catalytic residue at L191 (P = 0.078);

MVP

0.95

MPC

0.38

ClinPred

0.42

GERP RS

5.9

Varity_R

0.32

gMVP

0.72

Mutation Taster

=84/16

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over