rs66851495
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_000531.6(OTC):c.717G>A(p.Glu239=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
OTC
NM_000531.6 splice_region, synonymous
NM_000531.6 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 4.75
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.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-38408795-G-A is Pathogenic according to our data. Variant chrX-38408795-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97301.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.717G>A | p.Glu239= | splice_region_variant, synonymous_variant | 7/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.717G>A | p.Glu239= | splice_region_variant, synonymous_variant | 9/12 | ||
OTC | XM_017029556.2 | c.717G>A | p.Glu239= | splice_region_variant, synonymous_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.717G>A | p.Glu239= | splice_region_variant, synonymous_variant | 7/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*467G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 8/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
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 | Invitae | Jun 09, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 97301). This variant has been observed in individuals with clinical features of ornithine transcarbamylase deficiency (PMID: 9266388, 33369132; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 239 of the OTC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the OTC protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at