rs72554309

chrX-38367340-C-AchrX-38367340-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM5 PP3 BS2

The NM_000531.6(OTC):c.127C>A(p.Leu43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,200,139 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. L43F) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.0000092 (0 hom. 2 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.97

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 1 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000531.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38367340-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97108.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.127C>A	p.Leu43Ile	missense_variant	2/10	ENST00000039007.5
OTC	NM_001407092.1	c.127C>A	p.Leu43Ile	missense_variant	4/12
OTC	XM_017029556.2	c.127C>A	p.Leu43Ile	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.127C>A	p.Leu43Ile	missense_variant	2/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.219C>A		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1	c.127C>A	p.Leu43Ile	missense_variant, NMD_transcript_variant	2/11

Frequencies

GnomAD3 genomes AF: 0.0000896 AC: 10 AN: 111666 Hom.: 0 Cov.: 22 AF XY: 0.000118 AC XY: 4 AN XY: 33824

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000919 AC: 10 AN: 1088473 Hom.: 0 Cov.: 27 AF XY: 0.00000565 AC XY: 2 AN XY: 354173

Gnomad4 AFR exome AF: 0.000343

Gnomad4 AMR exome AF: 0.0000284

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 AF: 0.0000896 AC: 10 AN: 111666 Hom.: 0 Cov.: 22 AF XY: 0.000118 AC XY: 4 AN XY: 33824

Gnomad4 AFR AF: 0.000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000102

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 43 of the OTC protein (p.Leu43Ile). This variant is present in population databases (rs72554309, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with OTC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1348491). 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 expected to disrupt OTC protein function with a positive predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 23, 2022	This OTC variant (rs72554309) is rare (<0.1%) in a large population dataset (gnomAD: 2/21659 total alleles; 0.009%; 1 hemizygote –less than 30 years-old) and has been reported in ClinVar. A previously reported alternate pathogenic missense variant (p.Leu43Pro) occurs at this amino acid position. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated. The leucine residue at this position is strongly conserved across the vetrebrate species accessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.127C>A (p.Leu43Ile) to be uncertain at this time. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 04, 2023

Variant summary: OTC c.127C>A (p.Leu43Ile) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183119 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.127C>A in individuals affected with Ornithine Transcarbamylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.71
Sift	Benign	0.14	T
Sift4G	Benign	0.097	T
Polyphen		0.96	D
Vest4		0.67
MVP		0.75
MPC		1.2
ClinPred		0.79	D
GERP RS		2.6
Varity_R		0.65
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs72554309; hg19: chrX-38226593;