rs957415

Variant names:

• chrX-38403790-A-G
• rs957415
• NM_000531.6:c.663+50A>G

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.663+50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,164,513 control chromosomes in the GnomAD database, including 9 homozygotes. There are 1,613 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., 97 hem., cov: 23)
  • Exomes 𝑓: 0.0043 (8 hom. 1516 hem.)
• Consequence: OTC NM_000531.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209
• 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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-38403790-A-G is Benign according to our data. Variant chrX-38403790-A-G is described in ClinVar as Benign. ClinVar VariationId is 256371.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 = 0.00297 (332/111823) while in subpopulation NFE AF = 0.00485 (258/53158). AF 95% confidence interval is 0.00437. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 97 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.663+50A>G		intron	N/A	NP_000522.3
	OTC	NM_001407092.1		c.663+50A>G		intron	N/A	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.663+50A>G		intron	N/A	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262331A>G		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.663+50A>G		intron	N/A	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 332 AN: 111770 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000650

Gnomad AMI AF: 0.00438

Gnomad AMR AF: 0.00247

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00419

Gnomad FIN AF: 0.000657

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00403

GnomAD2 exomes AF: 0.00275 AC: 498 AN: 180767 AF XY: 0.00326

Gnomad AFR exome AF: 0.000613

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000906

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00433 AC: 4558 AN: 1052690 Hom.: 8 Cov.: 25 AF XY: 0.00470 AC XY: 1516 AN XY: 322506

African (AFR) AF: 0.000625 AC: 16 AN: 25581

American (AMR) AF: 0.00120 AC: 42 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.000105 AC: 2 AN: 19118

East Asian (EAS) AF: 0.00 AC: 0 AN: 29994

South Asian (SAS) AF: 0.00392 AC: 208 AN: 53048

European-Finnish (FIN) AF: 0.000999 AC: 40 AN: 40049

Middle Eastern (MID) AF: 0.00623 AC: 25 AN: 4013

European-Non Finnish (NFE) AF: 0.00507 AC: 4060 AN: 801124

Other (OTH) AF: 0.00370 AC: 165 AN: 44641

GnomAD4 genome AF: 0.00297 AC: 332 AN: 111823 Hom.: 1 Cov.: 23 AF XY: 0.00285 AC XY: 97 AN XY: 34019

African (AFR) AF: 0.000649 AC: 20 AN: 30822

American (AMR) AF: 0.00247 AC: 26 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00420 AC: 11 AN: 2618

European-Finnish (FIN) AF: 0.000657 AC: 4 AN: 6087

Middle Eastern (MID) AF: 0.0183 AC: 4 AN: 218

European-Non Finnish (NFE) AF: 0.00485 AC: 258 AN: 53158

Other (OTH) AF: 0.00398 AC: 6 AN: 1507

Alfa AF: 0.00386 Hom.: 32

Bravo AF: 0.00267

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.5
DANN	Benign	0.61
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs957415; hg19: chrX-38263043;