rs1800321

Variant names:

• chrX-38367350-A-G
• rs1800321
• NM_000531.6:c.137A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000531.6(OTC):​c.137A>G​(p.Lys46Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,200,554 control chromosomes in the GnomAD database, including 22,608 homozygotes. There are 82,733 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (3139 hom., 7685 hem., cov: 22)
  • Exomes 𝑓: 0.22 (19469 hom. 75048 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.43
• Publications: 31 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000531.6
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014624894).
• BP6: Variant X-38367350-A-G is Benign according to our data. Variant chrX-38367350-A-G is described in ClinVar as Benign. ClinVar VariationId is 10994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

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.137A>G	p.Lys46Arg	missense	Exon 2 of 10	NP_000522.3
	OTC	NM_001407092.1		c.137A>G	p.Lys46Arg	missense	Exon 4 of 12	NP_001394021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.137A>G	p.Lys46Arg	missense	Exon 2 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-298771A>G		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.137A>G	p.Lys46Arg	missense	Exon 4 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 28313 AN: 110592 Hom.: 3140 Cov.: 22

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.000836

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.302

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.187 AC: 34116 AN: 182760 AF XY: 0.180

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.000433

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.217 AC: 236649 AN: 1089911 Hom.: 19469 Cov.: 28 AF XY: 0.211 AC XY: 75048 AN XY: 356279

African (AFR) AF: 0.387 AC: 10145 AN: 26232

American (AMR) AF: 0.123 AC: 4316 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 5675 AN: 19323

East Asian (EAS) AF: 0.000497 AC: 15 AN: 30169

South Asian (SAS) AF: 0.0545 AC: 2940 AN: 53963

European-Finnish (FIN) AF: 0.173 AC: 6992 AN: 40503

Middle Eastern (MID) AF: 0.280 AC: 1155 AN: 4119

European-Non Finnish (NFE) AF: 0.234 AC: 195270 AN: 834588

Other (OTH) AF: 0.221 AC: 10141 AN: 45830

GnomAD4 genome AF: 0.256 AC: 28342 AN: 110643 Hom.: 3139 Cov.: 22 AF XY: 0.234 AC XY: 7685 AN XY: 32899

African (AFR) AF: 0.376 AC: 11398 AN: 30277

American (AMR) AF: 0.183 AC: 1897 AN: 10378

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 760 AN: 2632

East Asian (EAS) AF: 0.000838 AC: 3 AN: 3578

South Asian (SAS) AF: 0.0378 AC: 100 AN: 2649

European-Finnish (FIN) AF: 0.147 AC: 867 AN: 5878

Middle Eastern (MID) AF: 0.302 AC: 65 AN: 215

European-Non Finnish (NFE) AF: 0.239 AC: 12621 AN: 52839

Other (OTH) AF: 0.242 AC: 368 AN: 1519

Alfa AF: 0.245 Hom.: 30341

Bravo AF: 0.265

TwinsUK AF: 0.234 AC: 869

ALSPAC AF: 0.242 AC: 698

ESP6500AA AF: 0.376 AC: 1443

ESP6500EA AF: 0.241 AC: 1623

ExAC AF: 0.191 AC: 23146

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Ornithine carbamoyltransferase deficiency (5)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	ORNITHINE TRANSCARBAMYLASE POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.41
Sift	Benign	0.26	T
Sift4G	Benign	0.44	T
Polyphen		0.18	B
Vest4		0.14
MPC		0.39
ClinPred		0.043	T
GERP RS		4.2
Varity_R		0.31
gMVP		0.84
Mutation Taster		=92/8	polymorphism (auto)

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: rs1800321; hg19: chrX-38226603; COSMIC: COSV50000046;