Genetic Variant IDH1:p.Arg388Ser (chr2-208237162-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005896.4(IDH1):c.1162C>A(p.Arg388Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388C) has been classified 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: 7.60

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Maffucci syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

IDH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32613468).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005896.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDH1	NM_005896.4	MANE Select	c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	NP_005887.2
IDH1	NM_001282386.1		c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	NP_001269315.1	O75874
IDH1	NM_001282387.1		c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	NP_001269316.1	A0A024R3Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDH1	ENST00000345146.7	TSL:1 MANE Select	c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	ENSP00000260985.2	O75874
IDH1	ENST00000415913.5	TSL:1	c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	ENSP00000390265.1	O75874
IDH1	ENST00000446179.5	TSL:1	c.1162C>A	p.Arg388Ser	missense	Exon 10 of 10	ENSP00000410513.1	O75874

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

1445658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720154

African (AFR)

AF:

0.00

AC:

AN:

33166

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098012

Other (OTH)

AF:

0.00

AC:

AN:

59874

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.045

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.8

PhyloP100

7.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.97

REVEL

Uncertain

0.36

Sift

Benign

0.071

Sift4G

Benign

0.098

Polyphen

0.21

Vest4

0.51

MutPred

0.37

Loss of catalytic residue at R388 (P = 0.0221)

MVP

0.90

MPC

0.24

ClinPred

0.89

GERP RS

5.5

Varity_R

0.89

gMVP

0.91

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over