rs72558419

Positions:

• chrX-38403714-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000531.6(OTC):​c.637A>T​(p.Met213Leu) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M213K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.637A>T	p.Met213Leu	missense_variant	6/10	ENST00000039007.5
OTC	NM_001407092.1	c.637A>T	p.Met213Leu	missense_variant	8/12
OTC	XM_017029556.2	c.637A>T	p.Met213Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.637A>T	p.Met213Leu	missense_variant	6/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*387A>T		3_prime_UTR_variant, NMD_transcript_variant	7/11
OTC	ENST00000488812.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.69
Sift	Benign	0.050	D
Sift4G	Benign	0.17	T
Polyphen		0.72	P
Vest4		0.62
MutPred		0.66		Loss of ubiquitination at K210 (P = 0.1673);
MVP		0.98
MPC		0.47
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.82
gMVP		0.89

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: rs72558419; hg19: chrX-38262967;