rs72554348

Variant names:

• chrX-38369882-G-C
• rs72554348
• NM_000531.6:c.298+5G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-38369882-G-C
• chrX-38369882-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000531.6(OTC):​c.298+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,152,072 control chromosomes in the GnomAD database, including 1 homozygotes. There are 160 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., 21 hem., cov: 23)
  • Exomes 𝑓: 0.00041 (0 hom. 139 hem.)
• Consequence: OTC NM_000531.6 splice_region, intron
• Scores: Splicing: ADA: 0.5275
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:9
• Conservation: PhyloP100: 1.29
• Publications: 6 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: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-38369882-G-C is Benign according to our data. Variant chrX-38369882-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000677 (76/112240) while in subpopulation EAS AF = 0.0203 (73/3593). AF 95% confidence interval is 0.0166. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

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.298+5G>C		splice_region intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.298+5G>C		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.298+5G>C		splice_region intron	N/A	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-296239G>C		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.298+5G>C		splice_region intron	N/A	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 76 AN: 112191 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00162 AC: 296 AN: 183053 AF XY: 0.00145

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0211

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000406 AC: 422 AN: 1039832 Hom.: 0 Cov.: 22 AF XY: 0.000443 AC XY: 139 AN XY: 313636

African (AFR) AF: 0.000118 AC: 3 AN: 25359

American (AMR) AF: 0.0000285 AC: 1 AN: 35110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18988

East Asian (EAS) AF: 0.0117 AC: 350 AN: 29923

South Asian (SAS) AF: 0.000190 AC: 10 AN: 52751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3994

European-Non Finnish (NFE) AF: 0.00000760 AC: 6 AN: 789090

Other (OTH) AF: 0.00118 AC: 52 AN: 44193

GnomAD4 genome AF: 0.000677 AC: 76 AN: 112240 Hom.: 1 Cov.: 23 AF XY: 0.000610 AC XY: 21 AN XY: 34402

African (AFR) AF: 0.0000323 AC: 1 AN: 30936

American (AMR) AF: 0.0000946 AC: 1 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.0203 AC: 73 AN: 3593

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53308

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000759

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	5	Ornithine carbamoyltransferase deficiency (6)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
1	-	-	not provided (1)
-	-	1	OTC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		1.3
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: -5

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

Other links and lift over

dbSNP: rs72554348; hg19: chrX-38229135;