Genetic Variant OTC:p.Gly100Ala (chrX-38381342-G-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_000531.6(OTC):c.299G>C(p.Gly100Ala) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G100C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

OTC
NM_000531.6 missense, splice_region

Scores

Splicing: ADA: 0.1175

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

8 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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-38369877-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 870323.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, 0.938

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.299G>C	p.Gly100Ala	missense splice_region	Exon 4 of 10	NP_000522.3
	OTC	NM_001407092.1		c.299G>C	p.Gly100Ala	missense splice_region	Exon 6 of 12	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.299G>C	p.Gly100Ala	missense splice_region	Exon 4 of 10	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284779G>C		intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.299G>C	p.Gly100Ala	missense splice_region	Exon 6 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

0.91

PhyloP100

5.6

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.80

Sift

Benign

1.0

Sift4G

Benign

0.37

Polyphen

1.0

Vest4

0.59

MutPred

0.77

Loss of disorder (P = 0.1309)

MVP

0.96

MPC

1.2

ClinPred

0.97

GERP RS

5.8

Varity_R

0.88

gMVP

0.98

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.12

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.080

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

Computational scores

Splicing

Publications

Other links and lift over