rs72554328

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_000531.6(OTC):c.227T>C(p.Leu76Ser) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L76F) has been classified 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

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.27

Publications

4 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: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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-38369807-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496896.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.227T>C	p.Leu76Ser	missense_variant	Exon 3 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.227T>C	p.Leu76Ser	missense_variant	Exon 5 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.227T>C	p.Leu76Ser	missense_variant	Exon 3 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.227T>C	p.Leu76Ser	missense_variant	Exon 3 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-296315T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1061039

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

334169

African (AFR)

AF:

0.00

AC:

AN:

25794

American (AMR)

AF:

0.00

AC:

AN:

35129

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19122

East Asian (EAS)

AF:

0.00

AC:

AN:

29997

South Asian (SAS)

AF:

0.00

AC:

AN:

52986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4039

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

808735

Other (OTH)

AF:

0.00

AC:

AN:

44851

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Mar 21, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTC c.227T>C (p.Leu76Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182630 control chromosomes. c.227T>C has been reported in the literature in at least two individuals affected with Ornithine Transcarbamylase Deficiency (Genet_2000, Kido_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lo_2023). The following publications have been ascertained in the context of this evaluation (PMID: 11117428, 33851512, 37146589). ClinVar contains an entry for this variant (Variation ID: 97137). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.4

PhyloP100

6.3

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.97

REVEL

Pathogenic

0.77

Sift

Benign

0.88

Sift4G

Benign

0.37

Polyphen

0.99

Vest4

0.93

MutPred

0.84

Gain of disorder (P = 0.0062);

MVP

1.0

MPC

1.4

ClinPred

0.92

GERP RS

4.8

Varity_R

0.35

gMVP

0.97

Mutation Taster

=61/39

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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