rs36005267

Variant names:

• chrX-38408909-T-C
• rs36005267
• NM_000531.6:c.751T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000531.6(OTC):​c.751T>C​(p.Leu251Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,209,035 control chromosomes in the GnomAD database, including 21 homozygotes. There are 382 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 0.0068 (13 hom., 205 hem., cov: 23)
  • Exomes 𝑓: 0.00066 (8 hom. 177 hem.)
• Consequence: OTC NM_000531.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0560
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-38408909-T-C is Benign according to our data. Variant chrX-38408909-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.056 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00683 (760/111217) while in subpopulation AFR AF = 0.0239 (731/30570). AF 95% confidence interval is 0.0225. There are 13 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.751T>C	p.Leu251Leu	synonymous	Exon 8 of 10	NP_000522.3
	OTC	NM_001407092.1		c.751T>C	p.Leu251Leu	synonymous	Exon 10 of 12	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.751T>C	p.Leu251Leu	synonymous	Exon 8 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257212T>C		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.751T>C	p.Leu251Leu	synonymous	Exon 10 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 762 AN: 111163 Hom.: 13 Cov.: 23

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00333

GnomAD2 exomes AF: 0.00193 AC: 353 AN: 183251 AF XY: 0.00106

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000657 AC: 721 AN: 1097818 Hom.: 8 Cov.: 31 AF XY: 0.000487 AC XY: 177 AN XY: 363186

African (AFR) AF: 0.0216 AC: 571 AN: 26395

American (AMR) AF: 0.00142 AC: 50 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000273 AC: 23 AN: 841742

Other (OTH) AF: 0.00167 AC: 77 AN: 46090

GnomAD4 genome AF: 0.00683 AC: 760 AN: 111217 Hom.: 13 Cov.: 23 AF XY: 0.00613 AC XY: 205 AN XY: 33445

African (AFR) AF: 0.0239 AC: 731 AN: 30570

American (AMR) AF: 0.00210 AC: 22 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2626

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.000384 AC: 1 AN: 2605

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5991

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53022

Other (OTH) AF: 0.00329 AC: 5 AN: 1519

Alfa AF: 0.00542 Hom.: 55

Bravo AF: 0.00788

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Ornithine carbamoyltransferase deficiency (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.66
PhyloP100		-0.056
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs36005267; hg19: chrX-38268162;