rs67414444

chrX-38411938-T-AchrX-38411938-T-CchrX-38411938-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):c.944T>A(p.Val315Asp) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V315A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-38411937-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97365.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-38411938-T-A is Pathogenic according to our data. Variant chrX-38411938-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 97366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.944T>A	p.Val315Asp	missense_variant	9/10	ENST00000039007.5
OTC	NM_001407092.1	c.944T>A	p.Val315Asp	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.944T>A	p.Val315Asp	missense_variant	9/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*694T>A		3_prime_UTR_variant, NMD_transcript_variant	10/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2018	For these reasons, this variant has been classified as Pathogenic. Other different missense substitutions at this codon (p.Val315Gly, p.Val315Phe) have been reported in the literature in individuals affected with OTC deficieny (PMID: 10946359, 16786505). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with OTC deficiency (PMID: 10946359). Additionally, this variant has been observed to be de novo in an individual affected with OTC deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 97366). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 315 of the OTC protein (p.Val315Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	GenMed Metabolism Lab	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.80
Cadd	Pathogenic	27
Dann	Uncertain	0.97
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Gain of disorder (P = 0.0098);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs67414444; hg19: chrX-38271191;