rs68031618

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_000531.6(OTC):c.77G>A(p.Arg26Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

OTC
NM_000531.6 missense, splice_region

Scores

Splicing: ADA: 0.9174

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.65

Variant links:

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]

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a mutagenesis_site Loss of cleavage of the transit peptide and loss of localization to mitochondrial matrix; when associated with G-15 and G-23. (size 0) in uniprot entity OTC_HUMAN

PP5

Variant X-38352773-G-A is Pathogenic according to our data. Variant chrX-38352773-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38352773-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant, splice_region_variant	1/10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant, splice_region_variant	3/12		NP_001394021.1
OTC	XM_017029556.2 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant, splice_region_variant	1/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTC	ENST00000039007.5 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant, splice_region_variant	1/10	1	NM_000531.6	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-313348G>A		intron_variant		5		ENSP00000417050.1	B4E171
OTC	ENST00000488812.1 linkuse as main transcript	n.169G>A		splice_region_variant, non_coding_transcript_exon_variant	1/6	5
OTC	ENST00000643344.1 linkuse as main transcript	n.77G>A		splice_region_variant, non_coding_transcript_exon_variant	1/11			ENSP00000496606.1	A0A2R8Y829

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34176

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1066604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

334546

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

112038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34240

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1989	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2018	Variant summary: OTC c.77G>A (p.Arg26Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 86719 control chromosomes in ExAC and the literature. The c.77G>A variant has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (Grompe_1989, Kim_2006, Kim_2015, Arranz_2007, Shao_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 10993). This missense change has been observed in individual(s) with OTC deficiency (PMID: 2474822, 25994866). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 26 of the OTC protein (p.Arg26Gln). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2016

The c.77G>A variant (also known as p.R26Q), located in coding exon 1 of the OTC gene, results from a G to A substitution at nucleotide position 77. This change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the arginine at codon 26 to glutamine, an amino acid with highly similar properties. This variant was identified in a hemizygous state in a Hispanic male patient with neonatal clinical OTC deficiency. Analysis of a liver biopsy from this patient revealed lack of mRNA and enzyme activity (Grompe M et al. Proc. Natl. Acad. Sci. U.S.A. 1989 Aug;86(15):5888-92). This variant was previously reported in the SNPDatabase as rs68031618. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples with coverage at this position. Both the nucleotide and amino acid positions are not well conserved in available vertebrate species. Using the ESEfinder splice site prediction tool, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct experimental evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.74

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.34

REVEL

Uncertain

0.56

Sift

Benign

0.32

Sift4G

Benign

0.58

Polyphen

0.0020

Vest4

0.10

MutPred

0.87

Loss of MoRF binding (P = 0.0199);

MVP

0.97

MPC

0.43

ClinPred

0.19

GERP RS

3.8

Varity_R

0.10

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over