NM_000531.6:c.867+35T>G

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
• Publications: 3 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 -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 VariationId 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.867+35T>G		intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.867+35T>G		intron	N/A	NP_001394021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.867+35T>G		intron	N/A	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257061T>G		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.867+35T>G		intron	N/A	ENSP00000519059.1

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

African (AFR) AF: 0.00912 AC: 236 AN: 25874

American (AMR) AF: 0.0192 AC: 675 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 406 AN: 19206

East Asian (EAS) AF: 0.0000998 AC: 3 AN: 30060

South Asian (SAS) AF: 0.00636 AC: 340 AN: 53451

European-Finnish (FIN) AF: 0.0185 AC: 748 AN: 40499

Middle Eastern (MID) AF: 0.0429 AC: 173 AN: 4029

European-Non Finnish (NFE) AF: 0.0383 AC: 31267 AN: 815485

Other (OTH) 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

African (AFR) AF: 0.00885 AC: 272 AN: 30727

American (AMR) AF: 0.0285 AC: 301 AN: 10560

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 60 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00267 AC: 7 AN: 2617

European-Finnish (FIN) AF: 0.0164 AC: 100 AN: 6090

Middle Eastern (MID) AF: 0.0280 AC: 6 AN: 214

European-Non Finnish (NFE) AF: 0.0357 AC: 1892 AN: 53042

Other (OTH) AF: 0.0363 AC: 55 AN: 1517

Alfa AF: 0.0280 Hom.: 216

Bravo AF: 0.0264

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Ornithine carbamoyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		1.3
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

Other links and lift over

dbSNP: rs62622415; hg19: chrX-38268313;