rs72556280

Positions:

• chrX-38401404-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5

The NM_000531.6(OTC):​c.516C>G​(p.Ile172Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I172F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.520

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 Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chrX-38401402-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 97229.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant X-38401404-C-G is Pathogenic according to our data. Variant chrX-38401404-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 97230.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.516C>G	p.Ile172Met	missense_variant	5/10	ENST00000039007.5
OTC	NM_001407092.1	c.516C>G	p.Ile172Met	missense_variant	7/12
OTC	XM_017029556.2	c.516C>G	p.Ile172Met	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.516C>G	p.Ile172Met	missense_variant	5/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.553C>G		non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*266C>G		3_prime_UTR_variant, NMD_transcript_variant	6/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.81
Sift	Benign	0.051	T
Sift4G	Uncertain	0.030	D
Polyphen		0.96	D
Vest4		0.88
MutPred		0.87		Loss of catalytic residue at L177 (P = 0.0702);
MVP		1.0
MPC		1.2
ClinPred		0.82	D
GERP RS		2.9
Varity_R		0.90
gMVP		0.90

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: rs72556280; hg19: chrX-38260657;