rs72556262

chrX-38401318-A-GchrX-38401318-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000531.6(OTC):c.430A>G(p.Lys144Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000919 in 1,088,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.430A>G	p.Lys144Glu	missense_variant	5/10	ENST00000039007.5
OTC	NM_001407092.1	c.430A>G	p.Lys144Glu	missense_variant	7/12
OTC	XM_017029556.2	c.430A>G	p.Lys144Glu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.430A>G	p.Lys144Glu	missense_variant	5/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.467A>G		non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*180A>G		3_prime_UTR_variant, NMD_transcript_variant	6/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182397 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67027

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 9.19e-7 AC: 1 AN: 1088566 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 354306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.73	N
MutationTaster	Benign	0.90	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.47
Sift	Benign	0.34	T
Sift4G	Benign	0.84	T
Polyphen		0.0080	B
Vest4		0.60
MutPred		0.43		Loss of ubiquitination at K144 (P = 0.0381);
MVP		0.98
MPC		0.56
ClinPred		0.48	T
GERP RS		6.0
Varity_R		0.63
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs72556262; hg19: chrX-38260571;