rs66656800

Positions:

• chrX-38381429-G-A
• chrX-38381429-G-C
• chrX-38381429-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.386G>A​(p.Arg129His) variant causes a missense, splice region 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R129L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38381429-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 97182.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-38381429-G-A is Pathogenic according to our data. Variant chrX-38381429-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.386G>A	p.Arg129His	missense_variant, splice_region_variant	4/10	ENST00000039007.5
OTC	NM_001407092.1	c.386G>A	p.Arg129His	missense_variant, splice_region_variant	6/12
OTC	XM_017029556.2	c.386G>A	p.Arg129His	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.386G>A	p.Arg129His	missense_variant, splice_region_variant	4/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.423G>A		splice_region_variant, non_coding_transcript_exon_variant	4/6	5
OTC	ENST00000643344.1	c.*136G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	5/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1046247 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 318459

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 19, 2023	This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 umol/L). Elder brother of the proband had died at 6 month of age due to encephalopathy. This nucleotide change is absent from the gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.91 [PP3]. A clinvar entry [Variation id: 11010] of this variant is already present with a "Pathogenic" interpretation [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 04, 2019	This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that patients carrying this variant in the hemizygous state had reductions of OTC activity to less that 5% of normal levels (PMID: 7860064, 8081398). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.386G>A (p.Arg129His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.386G>A (p.Arg129His) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11010). This missense change has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 7860064, 8081398, 8807340, 25853564, 29581464, 30285816; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 129 of the OTC protein (p.Arg129His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.91
Sift	Benign	0.072	T
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.94		Gain of glycosylation at T127 (P = 0.0978);
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		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: rs66656800; hg19: chrX-38240682; COSMIC: COSV50001616;