rs55722856

chrX-38408862-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000531.6(OTC):c.718-14T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,208,527 control chromosomes in the GnomAD database, including 879 homozygotes. There are 3,338 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (461 hom., 1564 hem., cov: 22)
  • Exomes 𝑓: 0.0061 (418 hom. 1774 hem.)
• Consequence: OTC NM_000531.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.512

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-38408862-T-C is Benign according to our data. Variant chrX-38408862-T-C is described in ClinVar as [Benign]. Clinvar id is 93223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38408862-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.718-14T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000039007.5
OTC	NM_001407092.1	c.718-14T>C		splice_polypyrimidine_tract_variant, intron_variant
OTC	XM_017029556.2	c.718-14T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.718-14T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*468-14T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 6011 AN: 111052 Hom.: 461 Cov.: 22 AF XY: 0.0464 AC XY: 1545 AN XY: 33266

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00844

Gnomad SAS AF: 0.000766

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000528

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0168 AC: 3081 AN: 183273 Hom.: 216 AF XY: 0.0107 AC XY: 725 AN XY: 67799

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.00974

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00888

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00796

GnomAD4 exome AF: 0.00607 AC: 6663 AN: 1097423 Hom.: 418 Cov.: 30 AF XY: 0.00489 AC XY: 1774 AN XY: 362805

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00394

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0543 AC: 6034 AN: 111104 Hom.: 461 Cov.: 22 AF XY: 0.0469 AC XY: 1564 AN XY: 33328

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00847

Gnomad4 SAS AF: 0.000769

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000528

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.0317 Hom.: 198

Bravo AF: 0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.4
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55722856; hg19: chrX-38268115;