rs72558422

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000531.6(OTC):​c.645dup​(p.Gln216SerfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Consequence

OTC
NM_000531.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.63
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 Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-38403720-C-CT is Pathogenic according to our data. Variant chrX-38403720-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 97279.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTCNM_000531.6 linkuse as main transcriptc.645dup p.Gln216SerfsTer9 frameshift_variant 6/10 ENST00000039007.5
OTCNM_001407092.1 linkuse as main transcriptc.645dup p.Gln216SerfsTer9 frameshift_variant 8/12
OTCXM_017029556.2 linkuse as main transcriptc.645dup p.Gln216SerfsTer9 frameshift_variant 6/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTCENST00000039007.5 linkuse as main transcriptc.645dup p.Gln216SerfsTer9 frameshift_variant 6/101 NM_000531.6 P1
OTCENST00000643344.1 linkuse as main transcriptc.*395dup 3_prime_UTR_variant, NMD_transcript_variant 7/11

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
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 providedliterature onlyGenMed Metabolism Lab-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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: rs72558422; hg19: chrX-38262973; API