rs66737144

Variant names:

• chrX-38381430-G-A
• rs66737144
• NM_000531.6:c.386+1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38381430-G-A
• chrX-38381430-G-T

Variant summary

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

The NM_000531.6(OTC):​c.386+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.34

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38381430-G-A is Pathogenic according to our data. Variant chrX-38381430-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.386+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.386+1G>A		splice_donor_variant, intron_variant	Intron 6 of 11		NP_001394021.1
OTC	XM_017029556.2	c.386+1G>A		splice_donor_variant, intron_variant	Intron 4 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.386+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-284691G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000488812.1	n.423+1G>A		splice_donor_variant, intron_variant	Intron 4 of 5	5
OTC	ENST00000643344.1	n.*136+1G>A		splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Mar 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate skipping of exon 4 in a majority of transcripts (Sacchetto et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16786505, 34906067) -

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GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 3
DS_DL_spliceai		0.95		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs66737144; hg19: chrX-38240683;