Genetic Variant OTC:p.Pro225Ala (chrX-38408751-C-G) – 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.673C>G(p.Pro225Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000923 in 1,084,005 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. P225R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.47

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 11 ACMG points.

PM1

In a hotspot region, there are 5 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-38408752-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.673C>G	p.Pro225Ala	missense_variant	Exon 7 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.673C>G	p.Pro225Ala	missense_variant	Exon 9 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.673C>G	p.Pro225Ala	missense_variant	Exon 7 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.673C>G	p.Pro225Ala	missense_variant	Exon 7 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-257370C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.23e-7

AC:

AN:

1084005

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

351081

show subpopulations

African (AFR)

AF:

0.0000383

AC:

AN:

26126

American (AMR)

AF:

0.00

AC:

AN:

35183

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19282

East Asian (EAS)

AF:

0.00

AC:

AN:

30119

South Asian (SAS)

AF:

0.00

AC:

AN:

53812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829212

Other (OTH)

AF:

0.00

AC:

AN:

45657

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

5.5

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.80

Sift

Benign

0.55

Sift4G

Benign

0.45

Polyphen

0.95

Vest4

0.65

MutPred

0.83

Loss of methylation at K221 (P = 0.0586);

MVP

0.93

MPC

0.47

ClinPred

0.96

GERP RS

5.9

Varity_R

0.77

gMVP

0.95

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over