NM_000531.6:c.618G>A

Variant names:

• chrX-38403695-G-A
• rs72558413
• NM_000531.6:c.618G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Moderate PS3 PM1 PM2 PM5 PP2 PP5

The NM_000531.6(OTC):​c.618G>A​(p.Met206Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,096,986 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005398026: "moderate functional evidence supporting abnormal protein function. Biopsy of patient’s intestinal mucosa has shown only 5% of OTC activity (PMID:11793483). In addition, yeast complementation assay performed in S. cerevisiae has shown that this variant resulted in decreased yeast growth compared to wild-type (PMID:37146589)."". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M206K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.57
• Publications: 7 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 14 ACMG points.

• PS1: Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005398026: "moderate functional evidence supporting abnormal protein function. Biopsy of patient’s intestinal mucosa has shown only 5% of OTC activity (PMID: 11793483). In addition, yeast complementation assay performed in S. cerevisiae has shown that this variant resulted in decreased yeast growth compared to wild-type (PMID: 37146589)."
• PM1: In a hotspot region, there are 29 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-38403694-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 968929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant X-38403695-G-A is Pathogenic according to our data. Variant chrX-38403695-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1297045.

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.618G>A	p.Met206Ile	missense	Exon 6 of 10	NP_000522.3
	OTC	NM_001407092.1		c.618G>A	p.Met206Ile	missense	Exon 8 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.618G>A	p.Met206Ile	missense	Exon 6 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262426G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.618G>A	p.Met206Ile	missense	Exon 8 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183114 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096986 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362372

African (AFR) AF: 0.0000758 AC: 2 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840998

Other (OTH) AF: 0.00 AC: 0 AN: 46055

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Ornithine carbamoyltransferase deficiency (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	-0.12	N
PhyloP100		4.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.59
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.069	B
Vest4		0.45
MutPred		0.86		Gain of catalytic residue at M206 (P = 0.0428)
MVP		0.99
MPC		0.46
ClinPred		0.16	T
GERP RS		5.9
Varity_R		0.71
gMVP		0.88
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72558413; hg19: chrX-38262948; COSMIC: COSV50001850; COSMIC: COSV50001850;