X-38421078-T-G

Variant names:

• chrX-38421078-T-G
• rs72558495
• NM_000531.6:c.1061T>G
• OTC p.Phe354Cys

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5

The NM_000531.6(OTC):​c.1061T>G​(p.Phe354Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000423 in 1,181,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002766071: The variant resulted in approximately 30-35% activity versus the WT when assayed in vitro (Scharre_2022, Lo_2023), and the most pronounced variant effect was <2% of normal activity in an affected hemizygous individual (Yamaguchi_2006). PMID:10869432, 37146589, 32853555, 36217298, 11793468, 16786505".

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 6.65
• Publications: 5 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: ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002766071: The variant resulted in approximately 30-35% activity versus the WT when assayed in vitro (Scharre_2022, Lo_2023), and the most pronounced variant effect was <2% of normal activity in an affected hemizygous individual (Yamaguchi_2006). PMID: 10869432, 37146589, 32853555, 36217298, 11793468, 16786505
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant X-38421078-T-G is Pathogenic according to our data. Variant chrX-38421078-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97104.

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.1061T>G	p.Phe354Cys	missense	Exon 10 of 10	NP_000522.3
	OTC	NM_001407092.1		c.1061T>G	p.Phe354Cys	missense	Exon 12 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.1061T>G	p.Phe354Cys	missense	Exon 10 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-245043T>G		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.1061T>G	p.Phe354Cys	missense	Exon 12 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111431 Hom.: 0 Cov.: 23

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182812 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000374 AC: 4 AN: 1069717 Hom.: 0 Cov.: 25 AF XY: 0.00000296 AC XY: 1 AN XY: 337543

African (AFR) AF: 0.00 AC: 0 AN: 25886

American (AMR) AF: 0.00 AC: 0 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19186

East Asian (EAS) AF: 0.00 AC: 0 AN: 30083

South Asian (SAS) AF: 0.00 AC: 0 AN: 53475

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40393

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.00000490 AC: 4 AN: 816287

Other (OTH) AF: 0.00 AC: 0 AN: 45177

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111431 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33633

African (AFR) AF: 0.00 AC: 0 AN: 30651

American (AMR) AF: 0.00 AC: 0 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53036

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	1	-	Ornithine carbamoyltransferase deficiency (7)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.63
gMVP		0.96
Mutation Taster		=78/22	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72558495;

hg19: chrX-38280331;