rs72558452

chrX-38408971-AGAG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_000531.6(OTC):c.817_819del(p.Glu273del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000461 in 1,084,506 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.59

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000531.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-38408971-AGAG-A is Pathogenic according to our data. Variant chrX-38408971-AGAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.817_819del	p.Glu273del	inframe_deletion	8/10	ENST00000039007.5
OTC	NM_001407092.1	c.817_819del	p.Glu273del	inframe_deletion	10/12
OTC	XM_017029556.2	c.817_819del	p.Glu273del	inframe_deletion	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.817_819del	p.Glu273del	inframe_deletion	8/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*567_*569del		3_prime_UTR_variant, NMD_transcript_variant	9/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183136 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000461 AC: 5 AN: 1084506 Hom.: 0 AF XY: 0.00000281 AC XY: 1 AN XY: 355896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.00000240

Gnomad4 OTH exome AF: 0.0000442

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This variant causes an in-frame deletion of one amino acid (glutamic acid) at codon 273 of the OTC protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple male and female individuals affected with late-onset ornithine transcarbamylase deficiency (PMID: 8956045, 17334707, 25433810, 34014557, 35145162). This variant has also been observed de novo in a 1.5 month-old female affected with ornithine transcarbamylase deficiency (PMID: 17334707). This variant has been identified in 1/183136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This variant, c.817_819del, results in the deletion of 1 amino acid(s) of the OTC protein (p.Glu273del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs72558452, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8956045, 17334707, 25433810, 32420033, 34014557, 34014569). ClinVar contains an entry for this variant (Variation ID: 97337). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2024	Variant summary: OTC c.817_819delGAG (p.Glu273del) results in an in-frame deletion that is predicted to remove *** amino acids from the encoded protein. The variant allele was found at a frequency of 5.5e-06 in 183136 control chromosomes. c.817_819delGAG has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 97337). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2023	This variant causes an in-frame deletion of one amino acid (glutamic acid) at codon 273 of the OTC protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple male and female individuals affected with late-onset ornithine transcarbamylase deficiency (PMID: 8956045, 10799432, 17334707, 25433810, 34014557, 35145162). This variant has also been observed de novo in a 1.5 month-old female affected with ornithine transcarbamylase deficiency (PMID: 17334707). This variant has been identified in 1/183136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

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: rs72558452; hg19: chrX-38268224;