X-38352403-G-A

Variant names:

• chrX-38352403-G-A
• rs139948134
• ENST00000465127.1:c.172-313718G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000465127.1(ENSG00000250349):​c.172-313718G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 295,497 control chromosomes in the GnomAD database, including 17 homozygotes. There are 256 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (13 hom., 210 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (4 hom. 46 hem.)
• Consequence: ENSG00000250349 ENST00000465127.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.947
• Publications: 3 publications found

Genes affected

ENSG00000250349 (HGNC:):

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-38352403-G-A is Benign according to our data. Variant chrX-38352403-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1190289.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00701 (779/111206) while in subpopulation AFR AF = 0.0236 (721/30549). AF 95% confidence interval is 0.0222. There are 13 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_001407092.1	c.-79-215G>A		intron_variant	Intron 2 of 11		NP_001394021.1
OTC	NM_000531.6	c.-294G>A		upstream_gene_variant		ENST00000039007.5	NP_000522.3
OTC	XM_017029556.2	c.-294G>A		upstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-313718G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000039007.5	c.-294G>A		upstream_gene_variant		1	NM_000531.6	ENSP00000039007.4

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 775 AN: 111153 Hom.: 13 Cov.: 22

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00404

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00879

GnomAD4 exome AF: 0.00117 AC: 215 AN: 184291 Hom.: 4 AF XY: 0.000829 AC XY: 46 AN XY: 55461

African (AFR) AF: 0.0217 AC: 131 AN: 6034

American (AMR) AF: 0.00273 AC: 26 AN: 9540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5172

East Asian (EAS) AF: 0.000192 AC: 2 AN: 10399

South Asian (SAS) AF: 0.000137 AC: 3 AN: 21933

European-Finnish (FIN) AF: 0.000560 AC: 5 AN: 8936

Middle Eastern (MID) AF: 0.00143 AC: 1 AN: 699

European-Non Finnish (NFE) AF: 0.0000541 AC: 6 AN: 110873

Other (OTH) AF: 0.00383 AC: 41 AN: 10705

GnomAD4 genome AF: 0.00701 AC: 779 AN: 111206 Hom.: 13 Cov.: 22 AF XY: 0.00628 AC XY: 210 AN XY: 33458

African (AFR) AF: 0.0236 AC: 721 AN: 30549

American (AMR) AF: 0.00404 AC: 42 AN: 10399

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5901

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53091

Other (OTH) AF: 0.00868 AC: 13 AN: 1498

Alfa AF: 0.00712 Hom.: 24

Bravo AF: 0.00821

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.95
PromoterAI		-0.0068	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139948134; hg19: chrX-38211656;