rs957415

chrX-38403790-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.209

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 256371.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 97 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.663+50A>G		intron_variant		ENST00000039007.5
OTC	NM_001407092.1	c.663+50A>G		intron_variant
OTC	XM_017029556.2	c.663+50A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.663+50A>G		intron_variant		1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*413+50A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 332 AN: 111770 Hom.: 1 Cov.: 23 AF XY: 0.00286 AC XY: 97 AN XY: 33956

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

GnomAD3 exomes AF: 0.00275 AC: 498 AN: 180767 Hom.: 1 AF XY: 0.00326 AC XY: 215 AN XY: 65993

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 SAS exome AF: 0.00380

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

Gnomad4 AFR exome AF: 0.000625

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.000105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.000999

Gnomad4 NFE exome AF: 0.00507

Gnomad4 OTH exome AF: 0.00370

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

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00247

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00420

Gnomad4 FIN AF: 0.000657

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00398

Alfa AF: 0.00386 Hom.: 32

Bravo AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.5
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs957415; hg19: chrX-38263043;