chrX-38421026-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000531.6(OTC):c.1009G>T(p.Val337Phe) 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 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)
Consequence
OTC
NM_000531.6 missense
NM_000531.6 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 4.03
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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000531.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-38421026-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 97095.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.1009G>T | p.Val337Phe | missense_variant | 10/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.1009G>T | p.Val337Phe | missense_variant | 12/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.1009G>T | p.Val337Phe | missense_variant | 10/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*759G>T | 3_prime_UTR_variant, NMD_transcript_variant | 11/11 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant in c.1009G>T(p.Val337Phe) in OTC gene has been submitted to ClinVar as Pathogenic, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Val337Phe variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid Val at position 337 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. The amino acid change p.Val337Phe in OTC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | - | 2 boys with a neonatal form and 1 girl with a paroxysmal form - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.1042);
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