rs72554359
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000531.6(OTC):c.386+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
OTC
NM_000531.6 splice_donor
NM_000531.6 splice_donor
Scores
2
2
1
Splicing: ADA: 0.9995
2
Clinical Significance
Conservation
PhyloP100: 5.91
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 11 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-38381431-T-C is Pathogenic according to our data. Variant chrX-38381431-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 97180.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.386+2T>C | splice_donor_variant | ENST00000039007.5 | NP_000522.3 | |||
OTC | NM_001407092.1 | c.386+2T>C | splice_donor_variant | NP_001394021.1 | ||||
OTC | XM_017029556.2 | c.386+2T>C | splice_donor_variant | XP_016885045.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.386+2T>C | splice_donor_variant | 1 | NM_000531.6 | ENSP00000039007 | P1 | |||
OTC | ENST00000643344.1 | c.*136+2T>C | splice_donor_variant, NMD_transcript_variant | ENSP00000496606 | ||||||
OTC | ENST00000488812.1 | n.423+2T>C | splice_donor_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1021061Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 298385
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1021061
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Cov.:
23
AF XY:
AC XY:
0
AN XY:
298385
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
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
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
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_DG_spliceai
Position offset: 2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at