X-38352778-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_000531.6(OTC):​c.77+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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, intron

Scores

2
Splicing: ADA: 0.9998
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.08
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-38352778-G-C is Pathogenic according to our data. Variant chrX-38352778-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 870325.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTCNM_000531.6 linkc.77+5G>C splice_region_variant, intron_variant ENST00000039007.5 NP_000522.3 P00480
OTCNM_001407092.1 linkc.77+5G>C splice_region_variant, intron_variant NP_001394021.1
OTCXM_017029556.2 linkc.77+5G>C splice_region_variant, intron_variant XP_016885045.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTCENST00000039007.5 linkc.77+5G>C splice_region_variant, intron_variant 1 NM_000531.6 ENSP00000039007.4 P00480
ENSG00000250349ENST00000465127.1 linkc.172-313343G>C intron_variant 5 ENSP00000417050.1 B4E171
OTCENST00000488812.1 linkn.169+5G>C splice_region_variant, intron_variant 5
OTCENST00000643344.1 linkn.77+5G>C splice_region_variant, intron_variant ENSP00000496606.1 A0A2R8Y829

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
25
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:2
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 01, 2021This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of X-linked ornithine transcarbamylase deficiency (external communication, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 870325). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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. This sequence change falls in intron 1 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein. It affects a nucleotide within the consensus splice site of the intron. -
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics laboratory, Necker Hospital-a girl with a paroxysmal form -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.26
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72552302; hg19: chrX-38212031; API