rs72558488
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5
The NM_000531.6(OTC):c.1015G>A(p.Val339Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V339L) has been classified as Pathogenic.
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
8
7
2
Clinical Significance
Conservation
PhyloP100: 8.28
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000531.6
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-38421032-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 97096.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.779
PP5
?
Variant X-38421032-G-A is Pathogenic according to our data. Variant chrX-38421032-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 870333.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.1015G>A | p.Val339Met | missense_variant | 10/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.1015G>A | p.Val339Met | missense_variant | 12/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.1015G>A | p.Val339Met | missense_variant | 10/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*765G>A | 3_prime_UTR_variant, NMD_transcript_variant | 11/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1086088Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 352626
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1086088
Hom.:
Cov.:
26
AF XY:
AC XY:
0
AN XY:
352626
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | - | 1 girl with a paroxysmal form - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of helix (P = 0.1736);
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at