Genetic Variant OTC:p.His255Arg (chrX-38408922-A-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1PM5PP2BP4_ModerateBP6_ModerateBS2

The NM_000531.6(OTC):c.764A>G(p.His255Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000532 in 1,128,440 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H255P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000039 ( 0 hom. 3 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.388

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

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000531.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38408922-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97312.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.

BP4

Computational evidence support a benign effect (MetaRNN=0.11758301).

BP6

Variant X-38408922-A-G is Benign according to our data. Variant chrX-38408922-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1655516.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

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.764A>G	p.His255Arg	missense	Exon 8 of 10	NP_000522.3
	OTC	NM_001407092.1		c.764A>G	p.His255Arg	missense	Exon 10 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.764A>G	p.His255Arg	missense	Exon 8 of 10	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257199A>G		intron	N/A	ENSP00000417050.1	B4E171
OTC	ENST00000713758.1		c.764A>G	p.His255Arg	missense	Exon 10 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes

AF:

0.0000183

AC:

AN:

109530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183229

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000393

AC:

AN:

1018910

Hom.:

Cov.:

AF XY:

0.00000897

AC XY:

AN XY:

334328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23603

American (AMR)

AF:

0.00

AC:

AN:

32512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16016

East Asian (EAS)

AF:

0.00

AC:

AN:

24868

South Asian (SAS)

AF:

0.00

AC:

AN:

53346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3712

European-Non Finnish (NFE)

AF:

0.00000505

AC:

AN:

791874

Other (OTH)

AF:

0.00

AC:

AN:

40053

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000183

AC:

AN:

109530

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30197

American (AMR)

AF:

0.00

AC:

AN:

10233

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3140

South Asian (SAS)

AF:

0.00

AC:

AN:

2214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5949

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000379

AC:

AN:

52744

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ornithine carbamoyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.14

CADD

Benign

0.55

(source)

DANN

Benign

0.70

DEOGEN2

Uncertain

0.61

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.67

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

-1.9

PhyloP100

0.39

PrimateAI

Benign

0.21

PROVEAN

Benign

1.7

REVEL

Uncertain

0.50

Sift

Benign

0.39

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.14

MutPred

0.50

Loss of sheet (P = 0.1398)

MVP

0.89

MPC

0.45

ClinPred

0.027

GERP RS

-0.35

Varity_R

0.14

gMVP

0.70

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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