Genetic Variant NM_000531.6:c.421C>T (chrX-38401309-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000531.6(OTC):c.421C>T(p.Arg141*) variant causes a stop gained 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R141R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

OTC
NM_000531.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 3.63

Publications

16 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 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-38401309-C-T is Pathogenic according to our data. Variant chrX-38401309-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10988.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.421C>T	p.Arg141*	stop_gained	Exon 5 of 10	NP_000522.3
	OTC	NM_001407092.1		c.421C>T	p.Arg141*	stop_gained	Exon 7 of 12	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.421C>T	p.Arg141*	stop_gained	Exon 5 of 10	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-264812C>T		intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.421C>T	p.Arg141*	stop_gained	Exon 7 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1088844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354666

African (AFR)

AF:

0.00

AC:

AN:

26238

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19317

East Asian (EAS)

AF:

0.00

AC:

AN:

30121

South Asian (SAS)

AF:

0.00

AC:

AN:

53884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833796

Other (OTH)

AF:

0.00

AC:

AN:

45742

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000258

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:2

Jul 01, 1989

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Nov 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg141*) in the OTC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 10988). This premature translational stop signal has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 2741942, 3170748, 16786505, 18204299, 19138872, 25433810, 27070778).

not provided

Pathogenic:1

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.95

PhyloP100

3.6

Vest4

0.93

GERP RS

6.0

Mutation Taster

=0/200

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over