X-38369875-CAGGTA-C

Position:

• chrX-38369875-CAGGTA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000531.6(OTC):​c.298+1_298+5delGTAAG variant causes a splice donor, splice region, intron 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).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.81

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of 43, new splice context is: aagGTgaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38369875-CAGGTA-C is Pathogenic according to our data. Variant chrX-38369875-CAGGTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 97161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-38369875-CAGGTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.298+1_298+5delGTAAG		splice_donor_variant, splice_region_variant, intron_variant		ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.298+1_298+5delGTAAG		splice_donor_variant, splice_region_variant, intron_variant			NP_001394021.1
OTC	XM_017029556.2	c.298+1_298+5delGTAAG		splice_donor_variant, splice_region_variant, intron_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.298+1_298+5delGTAAG		splice_donor_variant, splice_region_variant, intron_variant		1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-296243_172-296239delGTAAG		intron_variant		5		ENSP00000417050.1
OTC	ENST00000488812.1	n.353+38_353+42delGTAAG		intron_variant		5
OTC	ENST00000643344.1	n.298+1_298+5delGTAAG		splice_donor_variant, splice_region_variant, intron_variant				ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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: rs111060773; hg19: chrX-38229128;