rs73196229

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-38381334-T-A
• chrX-38381334-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000531.6(OTC):​c.299-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,121,538 control chromosomes in the GnomAD database, including 16,616 homozygotes. There are 61,679 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1374 hom., 4103 hem., cov: 22)
  • Exomes 𝑓: 0.19 (15242 hom. 57576 hem.)
• Consequence: OTC NM_000531.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001725
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• 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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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).
• BP6: Variant X-38381334-T-A is Benign according to our data. Variant chrX-38381334-T-A is described in ClinVar as Benign. ClinVar VariationId is 93220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

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.299-8T>A		splice_region intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.299-8T>A		splice_region 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.299-8T>A		splice_region intron	N/A	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284787T>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.299-8T>A		splice_region intron	N/A	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.149 AC: 16397 AN: 110242 Hom.: 1375 Cov.: 22

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.000556

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.150 AC: 24614 AN: 164322 AF XY: 0.147

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.0901

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.000320

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.195 AC: 196936 AN: 1011239 Hom.: 15242 Cov.: 20 AF XY: 0.187 AC XY: 57576 AN XY: 307349

African (AFR) AF: 0.0364 AC: 873 AN: 24003

American (AMR) AF: 0.0994 AC: 3033 AN: 30517

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 4995 AN: 18143

East Asian (EAS) AF: 0.000468 AC: 14 AN: 29899

South Asian (SAS) AF: 0.0502 AC: 2469 AN: 49138

European-Finnish (FIN) AF: 0.170 AC: 6814 AN: 40072

Middle Eastern (MID) AF: 0.249 AC: 969 AN: 3884

European-Non Finnish (NFE) AF: 0.220 AC: 169758 AN: 772660

Other (OTH) AF: 0.187 AC: 8011 AN: 42923

GnomAD4 genome AF: 0.149 AC: 16389 AN: 110299 Hom.: 1374 Cov.: 22 AF XY: 0.126 AC XY: 4103 AN XY: 32589

African (AFR) AF: 0.0353 AC: 1083 AN: 30639

American (AMR) AF: 0.127 AC: 1302 AN: 10256

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 686 AN: 2610

East Asian (EAS) AF: 0.000558 AC: 2 AN: 3586

South Asian (SAS) AF: 0.0334 AC: 88 AN: 2631

European-Finnish (FIN) AF: 0.130 AC: 742 AN: 5688

Middle Eastern (MID) AF: 0.255 AC: 54 AN: 212

European-Non Finnish (NFE) AF: 0.227 AC: 11927 AN: 52517

Other (OTH) AF: 0.166 AC: 247 AN: 1489

Alfa AF: 0.138 Hom.: 1097

Bravo AF: 0.148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Ornithine carbamoyltransferase deficiency (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.83
PhyloP100		-0.10
BranchPoint Hunter		3.0
Mutation Taster		=36/64	disease causing (long InDel)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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;