X-38352649-G-T

Variant names:

• chrX-38352649-G-T
• rs182454762
• NM_000531.6:c.-48G>T

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.-48G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,013,723 control chromosomes in the GnomAD database, including 2 homozygotes. There are 278 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 0.00086 (0 hom., 45 hem., cov: 23)
  • Exomes 𝑓: 0.00083 (2 hom. 233 hem.)
• Consequence: OTC NM_000531.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-38352649-G-T is Benign according to our data. Variant chrX-38352649-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 368256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000859 (96/111783) while in subpopulation NFE AF = 0.000395 (21/53168). AF 95% confidence interval is 0.000264. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.-48G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_000531.6	c.-48G>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000039007.5	NP_000522.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.-48G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1	NM_000531.6	ENSP00000039007.4
OTC	ENST00000039007.5	c.-48G>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-313472G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 97 AN: 111727 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000560

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000395

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00143 AC: 256 AN: 179277 AF XY: 0.00120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000662

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00383

GnomAD4 exome AF: 0.000826 AC: 745 AN: 901940 Hom.: 2 Cov.: 15 AF XY: 0.000897 AC XY: 233 AN XY: 259832

African (AFR) AF: 0.00 AC: 0 AN: 22668

American (AMR) AF: 0.00 AC: 0 AN: 34913

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18090

East Asian (EAS) AF: 0.00346 AC: 101 AN: 29200

South Asian (SAS) AF: 0.00 AC: 0 AN: 50044

European-Finnish (FIN) AF: 0.0133 AC: 532 AN: 40127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3655

European-Non Finnish (NFE) AF: 0.000108 AC: 72 AN: 663593

Other (OTH) AF: 0.00101 AC: 40 AN: 39650

GnomAD4 genome AF: 0.000859 AC: 96 AN: 111783 Hom.: 0 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33957

African (AFR) AF: 0.00 AC: 0 AN: 30797

American (AMR) AF: 0.00 AC: 0 AN: 10497

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.0123 AC: 74 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000395 AC: 21 AN: 53168

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.000727 Hom.: 5

Bravo AF: 0.0000793

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Feb 16, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.78
PhyloP100		1.8
PromoterAI		-0.0062	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs182454762; hg19: chrX-38211902;