rs140966644

Positions:

chr10-124403829-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000274.4(OAT):c.740T>C(p.Met247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

OAT
NM_000274.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

Variant links:

Genes affected

OAT (HGNC:8091): (ornithine aminotransferase) This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]

OAT links:

OAT (HGNC:):

OAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01734832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OAT	NM_000274.4 linkuse as main transcript	c.740T>C	p.Met247Thr	missense_variant	6/10	ENST00000368845.6	NP_000265.1	P04181-1A0A140VJQ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OAT	ENST00000368845.6 linkuse as main transcript	c.740T>C	p.Met247Thr	missense_variant	6/10	1	NM_000274.4	ENSP00000357838.5	P04181-1
OAT	ENST00000539214.5 linkuse as main transcript	c.326T>C	p.Met109Thr	missense_variant	5/9	1		ENSP00000439042.1	P04181-2
OAT	ENST00000467675.5 linkuse as main transcript	n.541T>C		non_coding_transcript_exon_variant	5/7	5
OAT	ENST00000483711.1 linkuse as main transcript	n.*16T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.000191

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251476

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000104

AC:

152

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000805

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:

0.0000962

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000210

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000548

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ornithine aminotransferase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 247 of the OAT protein (p.Met247Thr). This variant is present in population databases (rs140966644, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with OAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 456523). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OAT protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.77

DANN

Benign

0.61

DEOGEN2

Uncertain

0.52

.;D

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

-0.86

.;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.14

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.22

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

.;B

Vest4

0.11

MVP

0.51

MPC

0.26

ClinPred

0.0057

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.077

gMVP

0.64

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