rs749748052

Variant names:

• chrX-38352591-C-A
• rs749748052
• ENST00000465127.1:c.172-313530C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38352591-C-A
• chrX-38352591-C-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NM_001407092.1(OTC):​c.-79-27C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000336 in 595,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000612171: Functional testing in cultured cells indicates reduced expression of reporter gene.; SCV002275107: Experimental studies have shown that this variant affects OTC function (PMID:29282796, 35605046).; SCV005044400: Functional studies have shown that this variant affects HNF4 binding. In HepG2 cells transfected with c.-106C>A plasmid, the relative lucierase actiivty was lower as compared to wild typer promoter sequence containing plasmid. PMID:29282796, 35605046, 35822098; SCV000885873: In vitro transfection of reporter constructs harboring c.-106C>A into liver-derived cell lines demonstrate mild to moderate reduction in OTC expression (Han 2022, Jang 2018).; SCV005080125: Published functional studies demonstrate a damaging effect as the variant was shown to reduce promoter activity to approximately 10% or 27% of wildtype in absence or presence of enhancer; authors concluded that the mild effect of this variant was the reason for the late onset and incomplete penetrance (PMID:35605046)".

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000021 (0 hom. 1 hem.)
• Consequence: OTC NM_001407092.1 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.04
• Publications: 5 publications found

Genes affected

ENSG00000250349 (HGNC:):

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)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000612171: Functional testing in cultured cells indicates reduced expression of reporter gene.; SCV002275107: Experimental studies have shown that this variant affects OTC function (PMID: 29282796, 35605046).; SCV005044400: Functional studies have shown that this variant affects HNF4 binding. In HepG2 cells transfected with c.-106C>A plasmid, the relative lucierase actiivty was lower as compared to wild typer promoter sequence containing plasmid. PMID: 29282796, 35605046, 35822098; SCV000885873: In vitro transfection of reporter constructs harboring c.-106C>A into liver-derived cell lines demonstrate mild to moderate reduction in OTC expression (Han 2022, Jang 2018).; SCV005080125: Published functional studies demonstrate a damaging effect as the variant was shown to reduce promoter activity to approximately 10% or 27% of wildtype in absence or presence of enhancer; authors concluded that the mild effect of this variant was the reason for the late onset and incomplete penetrance (PMID: 35605046)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352591-C-A is Pathogenic according to our data. Variant chrX-38352591-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 487338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407092.1. 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_001407092.1		c.-79-27C>A		intron	N/A	NP_001394021.1	P00480
	OTC	NM_000531.6	MANE Select	c.-106C>A		upstream_gene	N/A	NP_000522.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-313530C>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000909238.1		c.-106C>A		5_prime_UTR	Exon 1 of 10	ENSP00000579297.1
	OTC	ENST00000909239.1		c.-106C>A		5_prime_UTR	Exon 1 of 9	ENSP00000579298.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111786 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 1 AN: 483418 Hom.: 0 Cov.: 7 AF XY: 0.00000642 AC XY: 1 AN XY: 155650

African (AFR) AF: 0.00 AC: 0 AN: 14181

American (AMR) AF: 0.00 AC: 0 AN: 29392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14882

East Asian (EAS) AF: 0.00 AC: 0 AN: 24909

South Asian (SAS) AF: 0.00 AC: 0 AN: 39646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2211

European-Non Finnish (NFE) AF: 0.00000336 AC: 1 AN: 297378

Other (OTH) AF: 0.00 AC: 0 AN: 25340

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111840 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34010

African (AFR) AF: 0.00 AC: 0 AN: 30780

American (AMR) AF: 0.00 AC: 0 AN: 10517

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53203

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ornithine carbamoyltransferase deficiency (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.76
PhyloP100		1.0
PromoterAI		-0.084	Neutral
Mutation Taster		=103/197	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs749748052; hg19: chrX-38211844;