rs1555971000

Variant names:

• chrX-38352555-G-A
• rs1555971000
• ENST00000465127.1:c.172-313566G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM2 PP5_Moderate BP4

The NM_001407092.1(OTC):​c.-79-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001198711: Experimental studies have shown that this promoter change causes a reduction of OTC transcription (PMID:¬†29282796).".

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_001407092.1 intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.21
• Publications: 0 publications found

Genes affected

ENSG00000250349 (HGNC:):

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001198711: Experimental studies have shown that this promoter change causes a reduction of OTC transcription (PMID:¬†29282796).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352555-G-A is Pathogenic according to our data. Variant chrX-38352555-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 487342.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407092.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_001407092.1		c.-79-63G>A		intron	N/A	NP_001394021.1	P00480
	OTC	NM_000531.6	MANE Select	c.-142G>A		upstream_gene	N/A	NP_000522.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-313566G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000909238.1		c.-142G>A		5_prime_UTR	Exon 1 of 10	ENSP00000579297.1
	OTC	ENST00000909239.1		c.-142G>A		5_prime_UTR	Exon 1 of 9	ENSP00000579298.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Ornithine carbamoyltransferase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.89
PhyloP100		3.2
PromoterAI		-0.053	Neutral
Mutation Taster		=112/188	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555971000; hg19: chrX-38211808;