Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000531.6(OTC):c.674C>A(p.Pro225Gln) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225R) has been classified as 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

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.28

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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-38408752-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 97291.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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant X-38408752-C-A is Pathogenic according to our data. Variant chrX-38408752-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1067355.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.674C>A	p.Pro225Gln	missense	Exon 7 of 10	NP_000522.3
	OTC	NM_001407092.1		c.674C>A	p.Pro225Gln	missense	Exon 9 of 12	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.674C>A	p.Pro225Gln	missense	Exon 7 of 10	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257369C>A		intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.674C>A	p.Pro225Gln	missense	Exon 9 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1084890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

351744

African (AFR)

AF:

0.00

AC:

AN:

26147

American (AMR)

AF:

0.00

AC:

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19288

East Asian (EAS)

AF:

0.00

AC:

AN:

30124

South Asian (SAS)

AF:

0.00

AC:

AN:

53801

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830047

Other (OTH)

AF:

0.00

AC:

AN:

45681

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.69

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

PhyloP100

5.3

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.94

Sift

Benign

0.30

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.83

MutPred

0.82

Loss of methylation at K221 (P = 0.1197)

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

5.9

Varity_R

0.93

gMVP

0.98

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_000531.6:c.674C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over