Genetic Variant NM_000531.6:c.640C>T (chrX-38403717-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000531.6(OTC):c.640C>T(p.His214Tyr) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H214Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.15

Publications

6 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 10 ACMG points.

PM1

In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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, 0.969

PP5

Variant X-38403717-C-T is Pathogenic according to our data. Variant chrX-38403717-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 97277.Status of the report is no_assertion_criteria_provided, 0 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.640C>T	p.His214Tyr	missense	Exon 6 of 10	NP_000522.3
	OTC	NM_001407092.1		c.640C>T	p.His214Tyr	missense	Exon 8 of 12	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.640C>T	p.His214Tyr	missense	Exon 6 of 10	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262404C>T		intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.640C>T	p.His214Tyr	missense	Exon 8 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

2.1

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.88

Sift

Uncertain

0.028

Sift4G

Uncertain

0.031

Polyphen

0.98

Vest4

0.76

MutPred

0.81

Gain of phosphorylation at H214 (P = 0.0673)

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.80

gMVP

0.88

Mutation Taster

=72/28

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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