chrX-38381350-C-A

Variant names:

• chrX-38381350-C-A
• rs779154479
• NM_000531.6:c.307C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_000531.6(OTC):​c.307C>A​(p.Leu103Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,072,688 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L103F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000531.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.307C>A	p.Leu103Ile	missense	Exon 4 of 10	NP_000522.3
	OTC	NM_001407092.1		c.307C>A	p.Leu103Ile	missense	Exon 6 of 12	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.307C>A	p.Leu103Ile	missense	Exon 4 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284771C>A		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.307C>A	p.Leu103Ile	missense	Exon 6 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1072688 Hom.: 0 Cov.: 26 AF XY: 0.00000585 AC XY: 2 AN XY: 342112

African (AFR) AF: 0.00 AC: 0 AN: 25960

American (AMR) AF: 0.00 AC: 0 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19181

East Asian (EAS) AF: 0.00 AC: 0 AN: 30065

South Asian (SAS) AF: 0.00 AC: 0 AN: 52955

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819808

Other (OTH) AF: 0.0000221 AC: 1 AN: 45236

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000110

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.76
Sift	Benign	0.056	T
Sift4G	Benign	0.39	T
Polyphen		0.94	P
Vest4		0.51
MutPred		0.54		Loss of disorder (P = 0.1315)
MVP		0.81
MPC		1.1
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.81
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs779154479; hg19: chrX-38240603;