Variant 2-208237155-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005896.4(IDH1):c.1169A>G(p.Asp390Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IDH1
NM_005896.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63

Variant links:

Genes affected

IDH1 (HGNC:5382): (isocitrate dehydrogenase (NADP(+)) 1) 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. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

IDH1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH1	NM_005896.4 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10	ENST00000345146.7	NP_005887.2	O75874A0A024R3Y6
IDH1	NM_001282386.1 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10		NP_001269315.1	O75874A0A024R3Y6
IDH1	NM_001282387.1 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10		NP_001269316.1	O75874A0A024R3Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IDH1	ENST00000345146.7 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10	1	NM_005896.4	ENSP00000260985.2	O75874
IDH1	ENST00000415913.5 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10	1		ENSP00000390265.1	O75874
IDH1	ENST00000446179.5 link	c.1169A>G	p.Asp390Gly	missense_variant	10/10	1		ENSP00000410513.1	O75874
IDH1	ENST00000484575.1 link	n.631A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1452110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723072

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2024

The p.D390G variant (also known as c.1169A>G), located in coding exon 8 of the IDH1 gene, results from an A to G substitution at nucleotide position 1169. The aspartic acid at codon 390 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.073

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.93

P;P;P

Vest4

0.69

MutPred

0.23

Loss of stability (P = 0.0631);Loss of stability (P = 0.0631);Loss of stability (P = 0.0631);

MVP

0.89

MPC

0.64

ClinPred

0.92

GERP RS

5.5

Varity_R

0.54

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over