rs72558429
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000531.6(OTC):c.698C>T(p.Ala233Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A233A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
OTC
NM_000531.6 missense
NM_000531.6 missense
Scores
7
4
6
Clinical Significance
Conservation
PhyloP100: 4.41
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000531.6
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant X-38408776-C-T is Pathogenic according to our data. Variant chrX-38408776-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97293.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.698C>T | p.Ala233Val | missense_variant | 7/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.698C>T | p.Ala233Val | missense_variant | 9/12 | ||
OTC | XM_017029556.2 | c.698C>T | p.Ala233Val | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.698C>T | p.Ala233Val | missense_variant | 7/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*448C>T | 3_prime_UTR_variant, NMD_transcript_variant | 8/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1091767Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 357491
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1091767
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
357491
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 01, 2024 | - - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K238 (P = 0.0422);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 19
Find out detailed SpliceAI scores and Pangolin per-transcript scores at