X-38381324-C-A

Variant names:

• chrX-38381324-C-A
• rs5917586
• NM_000531.6:c.299-18C>A

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.299-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 106,590 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.19
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.299-18C>A		intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.299-18C>A		intron	N/A	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.299-18C>A		intron	N/A	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284797C>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.299-18C>A		intron	N/A	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.0000188 AC: 2 AN: 106590 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000682

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 832850 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 259792

African (AFR) AF: 0.00 AC: 0 AN: 19342

American (AMR) AF: 0.00 AC: 0 AN: 26021

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15165

East Asian (EAS) AF: 0.00 AC: 0 AN: 23106

South Asian (SAS) AF: 0.00 AC: 0 AN: 39218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3440

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 637588

Other (OTH) AF: 0.00 AC: 0 AN: 35054

GnomAD4 genome AF: 0.0000188 AC: 2 AN: 106590 Hom.: 0 Cov.: 23 AF XY: 0.0000327 AC XY: 1 AN XY: 30550

African (AFR) AF: 0.0000682 AC: 2 AN: 29340

American (AMR) AF: 0.00 AC: 0 AN: 9879

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2570

East Asian (EAS) AF: 0.00 AC: 0 AN: 3414

South Asian (SAS) AF: 0.00 AC: 0 AN: 2468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5071

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 231

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51528

Other (OTH) AF: 0.00 AC: 0 AN: 1430

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.061
DANN	Benign	0.28
PhyloP100		-3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5917586; hg19: chrX-38240577;