X-38381334-T-G

Variant names:

• chrX-38381334-T-G
• rs73196229
• NM_000531.6:c.299-8T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000531.6(OTC):​c.299-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,015,206 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000049 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001704
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.103
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.299-8T>G		splice_region intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.299-8T>G		splice_region intron	N/A	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.299-8T>G		splice_region intron	N/A	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284787T>G		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.299-8T>G		splice_region intron	N/A	ENSP00000519059.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000493 AC: 5 AN: 1015206 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 307826

African (AFR) AF: 0.00 AC: 0 AN: 24021

American (AMR) AF: 0.00 AC: 0 AN: 30569

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18207

East Asian (EAS) AF: 0.00 AC: 0 AN: 29899

South Asian (SAS) AF: 0.00 AC: 0 AN: 49169

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40101

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3893

European-Non Finnish (NFE) AF: 0.00000644 AC: 5 AN: 776289

Other (OTH) AF: 0.00 AC: 0 AN: 43058

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1097

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.78
PhyloP100		-0.10
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.010		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: rs73196229; hg19: chrX-38240587;