rs72558496

Positions:

• chrX-38352773-GGTAA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_Strong PM2 PP3_Moderate PP5

The NM_000531.6(OTC):​c.77+3_77+6del variant causes a splice donor, splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 splice_donor, splice_donor_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.08

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15868545 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 6, new splice context is: atgGTcaga. Cryptic site results in inframe 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-38352773-GGTAA-G is Pathogenic according to our data. Variant chrX-38352773-GGTAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 97315.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-38352773-GGTAA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.77+3_77+6del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000039007.5
OTC	NM_001407092.1	c.77+3_77+6del		splice_donor_variant, splice_donor_region_variant, intron_variant
OTC	XM_017029556.2	c.77+3_77+6del		splice_donor_variant, splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.77+3_77+6del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_000531.6	P1
OTC	ENST00000643344.1	c.77+3_77+6del		splice_donor_variant, splice_donor_region_variant, intron_variant, NMD_transcript_variant
OTC	ENST00000488812.1	n.169+3_169+6del		splice_donor_variant, splice_donor_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -14
DS_DL_spliceai		0.84		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558496; hg19: chrX-38212026;