rs5917586

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-38381324-C-T
• chrX-38381324-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000531.6(OTC):​c.299-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 832,805 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000084 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-38381324-C-T is Benign according to our data. Variant chrX-38381324-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000634 AC: 6 AN: 94661 AF XY: 0.00

Gnomad AFR exome AF: 0.000145

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000844

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000841 AC: 7 AN: 832805 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 259755

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000103 AC: 2 AN: 19340

American (AMR) AF: 0.0000384 AC: 1 AN: 26019

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15163

East Asian (EAS) AF: 0.00 AC: 0 AN: 23104

South Asian (SAS) AF: 0.00 AC: 0 AN: 39213

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: 0.00000471 AC: 3 AN: 637558

Other (OTH) AF: 0.0000285 AC: 1 AN: 35052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Ornithine carbamoyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.094
DANN	Benign	0.20
PhyloP100		-3.2

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs5917586; hg19: chrX-38240577; COSMIC: COSV50004749;