X-38421045-C-T

Variant names:

• chrX-38421045-C-T
• rs72558491
• NM_000531.6:c.1028C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000531.6(OTC):​c.1028C>T​(p.Thr343Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000918 in 1,089,773 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T343A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.56
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38421044-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3013580.
• 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, 0.857
• PP5: Variant X-38421045-C-T is Pathogenic according to our data. Variant chrX-38421045-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3251609.

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.1028C>T	p.Thr343Ile	missense	Exon 10 of 10	NP_000522.3
	OTC	NM_001407092.1		c.1028C>T	p.Thr343Ile	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.1028C>T	p.Thr343Ile	missense	Exon 10 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-245076C>T		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.1028C>T	p.Thr343Ile	missense	Exon 12 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089773 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 355737

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26245

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19311

East Asian (EAS) AF: 0.00 AC: 0 AN: 30147

South Asian (SAS) AF: 0.00 AC: 0 AN: 53982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40347

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834625

Other (OTH) AF: 0.0000218 AC: 1 AN: 45807

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
1	-	-	Ornithine carbamoyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.032	D
Polyphen		0.93	P
Vest4		0.62
MutPred		0.45		Loss of phosphorylation at T343 (P = 0.0279)
MVP		0.95
MPC		0.92
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.67
gMVP		0.85
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs72558491; hg19: chrX-38280298;