dbSNP rs72556262: OTC:p.Lys144Glu (chrX-38401318-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000531.6(OTC):c.430A>G(p.Lys144Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000919 in 1,088,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.65

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 7 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;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.430A>G	p.Lys144Glu	missense_variant	Exon 5 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.430A>G	p.Lys144Glu	missense_variant	Exon 7 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.430A>G	p.Lys144Glu	missense_variant	Exon 5 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.430A>G	p.Lys144Glu	missense_variant	Exon 5 of 10	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-264803A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182397

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.19e-7

AC:

AN:

1088566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26230

American (AMR)

AF:

0.0000284

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19321

East Asian (EAS)

AF:

0.00

AC:

AN:

30132

South Asian (SAS)

AF:

0.00

AC:

AN:

53870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833470

Other (OTH)

AF:

0.00

AC:

AN:

45771

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.73

PhyloP100

5.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.47

Sift

Benign

0.34

Sift4G

Benign

0.84

Polyphen

0.0080

Vest4

0.60

MutPred

0.43

Loss of ubiquitination at K144 (P = 0.0381);

MVP

0.98

MPC

0.56

ClinPred

0.48

GERP RS

6.0

Varity_R

0.63

gMVP

0.83

Mutation Taster

=82/18

polymorphism

(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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rs72556262

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over