X-153785886-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004135.4(IDH3G):​c.1168G>A​(p.Ala390Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000388 in 1,209,984 control chromosomes in the GnomAD database, including 1 homozygotes. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 25)
Exomes 𝑓: 0.000042 ( 1 hom. 10 hem. )

Consequence

IDH3G
NM_004135.4 missense

Scores

2
3
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62
Variant links:
Genes affected
IDH3G (HGNC:5386): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02639839).
BS2
High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IDH3GNM_004135.4 linkc.1168G>A p.Ala390Thr missense_variant Exon 13 of 13 ENST00000217901.10 NP_004126.1 P51553-1
IDH3GNM_174869.3 linkc.*263G>A 3_prime_UTR_variant Exon 12 of 12 NP_777358.1 P51553-2O15384

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDH3GENST00000217901.10 linkc.1168G>A p.Ala390Thr missense_variant Exon 13 of 13 1 NM_004135.4 ENSP00000217901.5 P51553-1

Frequencies

GnomAD3 genomes
AF:
0.00000888
AC:
1
AN:
112672
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
34818
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000929
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
GnomAD3 exomes
AF:
0.000197
AC:
36
AN:
182787
Hom.:
0
AF XY:
0.000133
AC XY:
9
AN XY:
67431
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00120
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:
0.00
Gnomad OTH exome
AF:
0.000664
GnomAD4 exome
AF:
0.0000419
AC:
46
AN:
1097312
Hom.:
1
Cov.:
33
AF XY:
0.0000275
AC XY:
10
AN XY:
363148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00128
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:
0.0000217
GnomAD4 genome
AF:
0.00000888
AC:
1
AN:
112672
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
34818
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000929
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
Alfa
AF:
0.0000897
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.000214
AC:
26

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 31, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1168G>A (p.A390T) alteration is located in exon 13 (coding exon 13) of the IDH3G gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the alanine (A) at amino acid position 390 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.026
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
0.49
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
0.020
N
REVEL
Benign
0.18
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.096
B
Vest4
0.13
MutPred
0.27
Loss of helix (P = 0.0558);
MVP
0.65
MPC
0.92
ClinPred
0.12
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.59

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.

Other links and lift over

dbSNP: rs781791676; hg19: chrX-153051341; API