NM_000531.6:c.622G>A

Variant names:

• chrX-38403699-G-A
• rs72558416
• NM_000531.6:c.622G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 21P and 4B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000531.6(OTC):​c.622G>A​(p.Ala208Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,096,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000617479: "Published functional studies support that this variant is associated with impaired OTC activity (PMID:37146589)"". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.31
• Publications: 18 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617479: "Published functional studies support that this variant is associated with impaired OTC activity (PMID: 37146589)"
• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38403699-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2083011.
• 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, 0.991
• PP5: Variant X-38403699-G-A is Pathogenic according to our data. Variant chrX-38403699-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

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.622G>A	p.Ala208Thr	missense	Exon 6 of 10	NP_000522.3
	OTC	NM_001407092.1		c.622G>A	p.Ala208Thr	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.622G>A	p.Ala208Thr	missense	Exon 6 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-262422G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.622G>A	p.Ala208Thr	missense	Exon 8 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096505 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 361931

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 840591

Other (OTH) AF: 0.00 AC: 0 AN: 46037

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Ornithine carbamoyltransferase deficiency (8)
4	-	-	not provided (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	Likely inborn error of metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of ubiquitination at K210 (P = 0.1621)
MVP		1.0
MPC		1.1
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.90
Mutation Taster		=20/80	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

Other links and lift over

dbSNP: rs72558416; hg19: chrX-38262952; COSMIC: COSV50001314; COSMIC: COSV50001314;