chrX-38352698-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_000531.6(OTC):c.2T>C(p.Met1?) variant causes a start lost 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
OTC
NM_000531.6 start_lost
NM_000531.6 start_lost
Scores
6
5
3
Clinical Significance
Conservation
PhyloP100: 4.04
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 14 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000531.6 (OTC) was described as [Pathogenic] in ClinVar as 97131
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-38352698-T-C is Pathogenic according to our data. Variant chrX-38352698-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 97164.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.2T>C | p.Met1? | start_lost | 1/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.2T>C | p.Met1? | start_lost | 3/12 | ||
OTC | XM_017029556.2 | c.2T>C | p.Met1? | start_lost | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.2T>C | p.Met1? | start_lost | 1/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000488812.1 | n.94T>C | non_coding_transcript_exon_variant | 1/6 | 5 | ||||
OTC | ENST00000643344.1 | c.2T>C | p.Met1? | start_lost, NMD_transcript_variant | 1/11 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 97164). Disruption of the initiator codon has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793483, 16786505, 33272297). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the OTC mRNA. The next in-frame methionine is located at codon p.Met21. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0066);
MVP
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