rs72554355

chrX-38381407-G-GTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000531.6(OTC):c.364_365insTT(p.Glu122ValfsTer66) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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-38381407-G-GTT is Pathogenic according to our data. Variant chrX-38381407-G-GTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97174.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.364_365insTT	p.Glu122ValfsTer66	frameshift_variant	4/10	ENST00000039007.5
OTC	NM_001407092.1	c.364_365insTT	p.Glu122ValfsTer66	frameshift_variant	6/12
OTC	XM_017029556.2	c.364_365insTT	p.Glu122ValfsTer66	frameshift_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.364_365insTT	p.Glu122ValfsTer66	frameshift_variant	4/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.401_402insTT		non_coding_transcript_exon_variant	4/6	5
OTC	ENST00000643344.1	c.*114_*115insTT		3_prime_UTR_variant, NMD_transcript_variant	5/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 23, 2020

Variant summary: OTC c.364_365insTT (p.Glu122ValfsX66) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182968 control chromosomes (gnomAD). c.364_365insTT has been reported in the literature in a heterozygous female (Yamaguchi_2006). This report does not provide unequivocal conclusions about association of the variant with Ornithine Transcarbamylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72554355; hg19: chrX-38240660;