rs281865553

chrX-38411999-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000531.6(OTC):c.1005G>A(p.Met335Ile) 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. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M335T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.49

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 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.1005G>A	p.Met335Ile	missense_variant, splice_region_variant	9/10	ENST00000039007.5
OTC	NM_001407092.1	c.1005G>A	p.Met335Ile	missense_variant, splice_region_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.1005G>A	p.Met335Ile	missense_variant, splice_region_variant	9/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*755G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	10/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

-

- -

Ornithine carbamoyltransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2022

This sequence change affects codon 335 of the OTC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the OTC protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793468, 30175132). ClinVar contains an entry for this variant (Variation ID: 97091). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.94
Sift	Benign	0.48	T
Sift4G	Benign	0.84	T
Polyphen		0.98	D
Vest4		0.91
MutPred		0.90		Loss of catalytic residue at M335 (P = 6e-04);
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		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: rs281865553; hg19: chrX-38271252;