rs72558487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM5PP2BS2

The NM_000531.6(OTC):c.1009G>A(p.Val337Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000184 in 1,084,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V337L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Publications

5 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000531.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38421026-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97095.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.

BS2

High Hemizygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.1009G>A	p.Val337Ile	missense	Exon 10 of 10	NP_000522.3
	OTC	NM_001407092.1		c.1009G>A	p.Val337Ile	missense	Exon 12 of 12	NP_001394021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTC	ENST00000039007.5	TSL:1 MANE Select	c.1009G>A	p.Val337Ile	missense	Exon 10 of 10	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-245095G>A		intron	N/A	ENSP00000417050.1
OTC	ENST00000713758.1		c.1009G>A	p.Val337Ile	missense	Exon 12 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084196

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

351094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26139

American (AMR)

AF:

0.00

AC:

AN:

35187

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19278

East Asian (EAS)

AF:

0.00

AC:

AN:

30120

South Asian (SAS)

AF:

0.00

AC:

AN:

53858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40187

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.00000241

AC:

AN:

829722

Other (OTH)

AF:

0.00

AC:

AN:

45606

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

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

0.12

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.52

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.3

PhyloP100

4.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.60

Sift

Benign

0.037

Sift4G

Benign

0.30

Polyphen

0.52

Vest4

0.23

MutPred

0.73

Loss of catalytic residue at V337 (P = 0.0612)

MVP

0.98

MPC

0.38

ClinPred

0.67

GERP RS

4.5

Varity_R

0.23

gMVP

0.65

Mutation Taster

=55/45

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over