rs72556273

Positions:

• chrX-38401378-T-A
• chrX-38401378-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000531.6(OTC):​c.490T>A​(p.Ser164Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.490T>A	p.Ser164Thr	missense_variant	5/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.490T>A	p.Ser164Thr	missense_variant	7/12		NP_001394021.1
OTC	XM_017029556.2	c.490T>A	p.Ser164Thr	missense_variant	5/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.490T>A	p.Ser164Thr	missense_variant	5/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-264743T>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.63	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.74
Sift	Benign	0.074	T
Sift4G	Benign	0.71	T
Polyphen		1.0	D
Vest4		0.81
MVP		0.94
MPC		1.1
ClinPred		0.86	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.93

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: rs72556273; hg19: chrX-38260631;