Genetic Variant OTC:p.Asp165Asn (chrX-38401381-G-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

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

The NM_000531.6(OTC):c.493G>A(p.Asp165Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,093,451 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. D165G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.52

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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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-38401382-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 452381.

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, 0.97

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.493G>A	p.Asp165Asn	missense	Exon 5 of 10	NP_000522.3
	OTC	NM_001407092.1		c.493G>A	p.Asp165Asn	missense	Exon 7 of 12	NP_001394021.1	P00480

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTC	ENST00000039007.5	TSL:1 MANE Select	c.493G>A	p.Asp165Asn	missense	Exon 5 of 10	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-264740G>A		intron	N/A	ENSP00000417050.1	B4E171
OTC	ENST00000713758.1		c.493G>A	p.Asp165Asn	missense	Exon 7 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1093451

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

358945

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26317

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19349

East Asian (EAS)

AF:

0.00

AC:

AN:

30175

South Asian (SAS)

AF:

0.00

AC:

AN:

54032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

837784

Other (OTH)

AF:

0.00

AC:

AN:

45939

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

PhyloP100

6.5

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.78

Sift

Uncertain

0.016

Sift4G

Uncertain

0.018

Polyphen

0.98

Vest4

0.50

MutPred

0.91

Loss of catalytic residue at D165 (P = 0.1018)

MVP

0.87

MPC

0.70

ClinPred

0.98

GERP RS

6.0

Varity_R

0.79

gMVP

0.91

Mutation Taster

=45/55

disease causing

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over