rs62622415

Variant names:

• chrX-38409060-T-G
• rs62622415
• NM_000531.6:c.867+35T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000531.6(OTC):​c.867+35T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,180,579 control chromosomes in the GnomAD database, including 483 homozygotes. There are 11,736 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (29 hom., 738 hem., cov: 22)
  • Exomes 𝑓: 0.033 (454 hom. 10998 hem.)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.30

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]

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant X-38409060-T-G is Benign according to our data. Variant chrX-38409060-T-G is described in ClinVar as [Benign]. Clinvar id is 256372.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 = 0.0242 (2706/111645) while in subpopulation NFE AF = 0.0357 (1892/53042). AF 95% confidence interval is 0.0343. There are 29 homozygotes in GnomAd4. There are 738 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.867+35T>G		intron_variant	Intron 8 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.867+35T>G		intron_variant	Intron 10 of 11		NP_001394021.1
OTC	XM_017029556.2	c.867+35T>G		intron_variant	Intron 8 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.867+35T>G		intron_variant	Intron 8 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257061T>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*617+35T>G		intron_variant	Intron 9 of 10			ENSP00000496606.1

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 2712 AN: 111591 Hom.: 29 Cov.: 22

Gnomad AFR AF: 0.00890

Gnomad AMI AF: 0.0189

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0383

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0374

GnomAD2 exomes AF: 0.0231 AC: 4179 AN: 181276 AF XY: 0.0224

Gnomad AFR exome AF: 0.00931

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0330 AC: 35242 AN: 1068934 Hom.: 454 Cov.: 27 AF XY: 0.0326 AC XY: 10998 AN XY: 337042

Gnomad4 AFR exome AF: 0.00912 AC: 236 AN: 25874

Gnomad4 AMR exome AF: 0.0192 AC: 675 AN: 35164

Gnomad4 ASJ exome AF: 0.0211 AC: 406 AN: 19206

Gnomad4 EAS exome AF: 0.0000998 AC: 3 AN: 30060

Gnomad4 SAS exome AF: 0.00636 AC: 340 AN: 53451

Gnomad4 FIN exome AF: 0.0185 AC: 748 AN: 40499

Gnomad4 NFE exome AF: 0.0383 AC: 31267 AN: 815485

Gnomad4 Remaining exome AF: 0.0309 AC: 1394 AN: 45166

GnomAD4 genome AF: 0.0242 AC: 2706 AN: 111645 Hom.: 29 Cov.: 22 AF XY: 0.0218 AC XY: 738 AN XY: 33833

Gnomad4 AFR AF: 0.00885 AC: 0.00885215 AN: 0.00885215

Gnomad4 AMR AF: 0.0285 AC: 0.0285038 AN: 0.0285038

Gnomad4 ASJ AF: 0.0227 AC: 0.0227015 AN: 0.0227015

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00267 AC: 0.00267482 AN: 0.00267482

Gnomad4 FIN AF: 0.0164 AC: 0.0164204 AN: 0.0164204

Gnomad4 NFE AF: 0.0357 AC: 0.0356698 AN: 0.0356698

Gnomad4 OTH AF: 0.0363 AC: 0.0362558 AN: 0.0362558

Alfa AF: 0.0280 Hom.: 216

Bravo AF: 0.0264

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ornithine carbamoyltransferase deficiency Benign:1

Sep 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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	-0.23
CADD	Benign	16
DANN	Benign	0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs62622415; hg19: chrX-38268313;