chrX-38352745-GGTCA-G

Position:

• chrX-38352745-GGTCA-G

Variant summary

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

The NM_000531.6(OTC):​c.50_53del​(p.Gly17AlafsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.29

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 414 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352745-GGTCA-G is Pathogenic according to our data. Variant chrX-38352745-GGTCA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1726983.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.50_53del	p.Gly17AlafsTer20	frameshift_variant	1/10	ENST00000039007.5
OTC	NM_001407092.1	c.50_53del	p.Gly17AlafsTer20	frameshift_variant	3/12
OTC	XM_017029556.2	c.50_53del	p.Gly17AlafsTer20	frameshift_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.50_53del	p.Gly17AlafsTer20	frameshift_variant	1/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.142_145del		non_coding_transcript_exon_variant	1/6	5
OTC	ENST00000643344.1	c.50_53del	p.Gly17AlafsTer20	frameshift_variant, NMD_transcript_variant	1/11

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 06, 2022

NM_000531.5(OTC):c.50_53delGTCA(G17Afs*20) is expected to be pathogenic in the context of ornithine transcarbamylase deficiency. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in OTC, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38211998;