X-38352750-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000531.6(OTC):c.54C>A(p.His18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,211 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. H18N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.180

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074592024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.54C>A	p.His18Gln	missense_variant	1/10	ENST00000039007.5
OTC	NM_001407092.1	c.54C>A	p.His18Gln	missense_variant	3/12
OTC	XM_017029556.2	c.54C>A	p.His18Gln	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.54C>A	p.His18Gln	missense_variant	1/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.146C>A		non_coding_transcript_exon_variant	1/6	5
OTC	ENST00000643344.1	c.54C>A	p.His18Gln	missense_variant, NMD_transcript_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093211 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 358727

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OTC protein function. This variant has not been reported in the literature in individuals affected with OTC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the OTC protein (p.His18Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.48
Dann	Benign	0.61
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.075	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.39		Gain of helix (P = 0.0199);
MVP		0.36
MPC		0.37
ClinPred		0.026	T
GERP RS		4.0
Varity_R		0.076
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38212003;