rs67939655

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM5BP6BS2

The NM_000531.6(OTC):c.140A>C(p.Asn47Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,198,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 55 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00014 ( 0 hom. 53 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 4.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000531.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38367353-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 97113.Status of the report is criteria_provided_single_submitter, 1 stars.

BP6

Variant X-38367353-A-C is Benign according to our data. Variant chrX-38367353-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97112.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
OTC	NM_000531.6 linkuse as main transcript	c.140A>C	p.Asn47Thr	missense_variant	2/10	ENST00000039007.5
OTC	NM_001407092.1 linkuse as main transcript	c.140A>C	p.Asn47Thr	missense_variant	4/12
OTC	XM_017029556.2 linkuse as main transcript	c.140A>C	p.Asn47Thr	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
OTC	ENST00000039007.5 linkuse as main transcript	c.140A>C	p.Asn47Thr	missense_variant	2/10	1	NM_000531.6	P1
OTC	ENST00000488812.1 linkuse as main transcript	n.232A>C		non_coding_transcript_exon_variant	2/6	5
OTC	ENST00000643344.1 linkuse as main transcript	c.140A>C	p.Asn47Thr	missense_variant, NMD_transcript_variant	2/11

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111423

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

33589

show subpopulations

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:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000158

AC:

AN:

183170

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

67772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000312

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000144

AC:

157

AN:

1086654

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

352460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000382

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:

0.000617

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.000108

AC:

AN:

111423

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

33589

show subpopulations

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:

0.000167

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Uncertain:3Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 25, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2020

The p.Asn47Thr variant in OTC is classified as likely benign because although it has been reported in 1 female with ornithine transcarbamylase (OTC) deficiency (PMID 16786505), it has also been identified in 14/75447 hemizygous males in gnomAD (http://gnomad.broadinstitute.org), which is an allele frequency too high to cause OTC deficiency. ACMG/AMP criteria applied:BS1, BS4. -

OTC-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.99

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Polyphen

0.070

Vest4

0.73

MVP

0.90

MPC

0.41

ClinPred

0.083

GERP RS

5.4

Varity_R

0.52

gMVP

0.92

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

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