chrX-38401332-G-A

Variant names:

• chrX-38401332-G-A
• rs66741318
• NM_000531.6:c.444G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000531.6(OTC):​c.444G>A​(p.Leu148Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000185 in 1,082,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• 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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.444G>A	p.Leu148Leu	synonymous	Exon 5 of 10	NP_000522.3
	OTC	NM_001407092.1		c.444G>A	p.Leu148Leu	synonymous	Exon 7 of 12	NP_001394021.1	P00480

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.444G>A	p.Leu148Leu	synonymous	Exon 5 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-264789G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.444G>A	p.Leu148Leu	synonymous	Exon 7 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082045 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 348177

African (AFR) AF: 0.00 AC: 0 AN: 26107

American (AMR) AF: 0.00 AC: 0 AN: 35180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19282

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30101

South Asian (SAS) AF: 0.00 AC: 0 AN: 53672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 827540

Other (OTH) AF: 0.00 AC: 0 AN: 45596

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.7
DANN	Benign	0.76
PhyloP100		3.8

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: rs66741318; hg19: chrX-38260585;