NM_000531.6:c.650C>G

Variant names:

• chrX-38403727-C-G
• rs72558424
• NM_000531.6:c.650C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000531.6(OTC):​c.650C>G​(p.Ala217Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,184 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A217E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.56
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 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-38403727-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97280.Status of the report is no_assertion_criteria_provided, 0 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

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.650C>G	p.Ala217Gly	missense	Exon 6 of 10	NP_000522.3
	OTC	NM_001407092.1		c.650C>G	p.Ala217Gly	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.650C>G	p.Ala217Gly	missense	Exon 6 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262394C>G		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.650C>G	p.Ala217Gly	missense	Exon 8 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097184 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362574

African (AFR) AF: 0.0000379 AC: 1 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841190

Other (OTH) AF: 0.00 AC: 0 AN: 46059

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.28	B
Vest4		0.59
MutPred		0.68		Gain of disorder (P = 0.0769)
MVP		0.99
MPC		0.56
ClinPred		0.97	D
GERP RS		1.6
Varity_R		0.85
gMVP		0.91
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs72558424; hg19: chrX-38262980;