X-38408967-A-G

Variant names:

• chrX-38408967-A-G
• rs1800328
• NM_000531.6:c.809A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 6P and 20B. PM1 PM5 PP2 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000531.6(OTC):​c.809A>G​(p.Gln270Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,209,760 control chromosomes in the GnomAD database, including 650 homozygotes. There are 14,071 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q270E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (54 hom., 856 hem., cov: 22)
  • Exomes 𝑓: 0.037 (596 hom. 13215 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 8.81
• Publications: 22 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 -14 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000531.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38408967-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97336.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: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.019725591).
• BP6: Variant X-38408967-A-G is Benign according to our data. Variant chrX-38408967-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0285 (3186/111948) while in subpopulation NFE AF = 0.0425 (2260/53122). AF 95% confidence interval is 0.0411. There are 54 homozygotes in GnomAd4. There are 856 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 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.809A>G	p.Gln270Arg	missense	Exon 8 of 10	NP_000522.3
	OTC	NM_001407092.1		c.809A>G	p.Gln270Arg	missense	Exon 10 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.809A>G	p.Gln270Arg	missense	Exon 8 of 10	ENSP00000039007.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-257154A>G		intron	N/A	ENSP00000417050.1
	OTC	ENST00000713758.1		c.809A>G	p.Gln270Arg	missense	Exon 10 of 12	ENSP00000519059.1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 3188 AN: 111895 Hom.: 54 Cov.: 22

Gnomad AFR AF: 0.00530

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0341

GnomAD2 exomes AF: 0.0295 AC: 5395 AN: 183102 AF XY: 0.0305

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0371 AC: 40711 AN: 1097812 Hom.: 596 Cov.: 32 AF XY: 0.0364 AC XY: 13215 AN XY: 363224

African (AFR) AF: 0.00436 AC: 115 AN: 26397

American (AMR) AF: 0.0191 AC: 672 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 576 AN: 19379

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30198

South Asian (SAS) AF: 0.0117 AC: 632 AN: 54142

European-Finnish (FIN) AF: 0.0352 AC: 1426 AN: 40524

Middle Eastern (MID) AF: 0.0501 AC: 207 AN: 4135

European-Non Finnish (NFE) AF: 0.0421 AC: 35414 AN: 841751

Other (OTH) AF: 0.0362 AC: 1666 AN: 46084

GnomAD4 genome AF: 0.0285 AC: 3186 AN: 111948 Hom.: 54 Cov.: 22 AF XY: 0.0251 AC XY: 856 AN XY: 34114

African (AFR) AF: 0.00528 AC: 163 AN: 30847

American (AMR) AF: 0.0311 AC: 328 AN: 10561

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 99 AN: 2638

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3559

South Asian (SAS) AF: 0.0116 AC: 31 AN: 2669

European-Finnish (FIN) AF: 0.0293 AC: 180 AN: 6138

Middle Eastern (MID) AF: 0.0323 AC: 7 AN: 217

European-Non Finnish (NFE) AF: 0.0425 AC: 2260 AN: 53122

Other (OTH) AF: 0.0336 AC: 51 AN: 1516

Alfa AF: 0.0354 Hom.: 2914

Bravo AF: 0.0291

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0436 AC: 126

ESP6500AA AF: 0.00574 AC: 22

ESP6500EA AF: 0.0489 AC: 329

ExAC AF: 0.0299 AC: 3627

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	8	Ornithine carbamoyltransferase deficiency (9)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.26
MPC		0.94
ClinPred		0.026	T
GERP RS		5.6
Varity_R		0.90
gMVP		0.95
Mutation Taster		=95/5	polymorphism (auto)

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: rs1800328; hg19: chrX-38268220; COSMIC: COSV50005143;