X-38403663-G-T

Position:

• chrX-38403663-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM2 PM5 PP3_Strong PP5_Moderate

The NM_000531.6(OTC):​c.586G>T​(p.Asp196Tyr) 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. Variant has been reported in ClinVar as Likely pathogenic (★). 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. D196V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.54

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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, 0.996
• PP5: Variant X-38403663-G-T is Pathogenic according to our data. Variant chrX-38403663-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97258.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.586G>T	p.Asp196Tyr	missense_variant	6/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.586G>T	p.Asp196Tyr	missense_variant	8/12		NP_001394021.1
OTC	XM_017029556.2	c.586G>T	p.Asp196Tyr	missense_variant	6/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.586G>T	p.Asp196Tyr	missense_variant	6/10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262458G>T		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Sep 19, 2023

This sequence variant is a single nucleotide substitution (G>T) at position 586 of the coding sequence of the OTC gene that results in a aspartic acid to tyrosine amino acid change at residue 196 of the ornithine transcarbamylase protein. This is a previously reported variant (ClinVar 97258) that has been observed in individuals affected by ornithine transcarbamylase deficiency (PMID: 9686344, 17044854). This variant is absent from the gnomAD population database (0/~200,000 alleles). Multiple bioinformatic tools predict that this Asp to Tyr amino acid change would be damaging, and the Asp196 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge; however missense mutation is a common mechanism of disease for OTC, and different variants at this position have been previously considered pathogenic. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP2, PP3, PS4 -

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Gain of sheet (P = 0.1208);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		1.0
gMVP		0.99

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: rs66642398; hg19: chrX-38262916;