Genetic Variant IDH1:p.Tyr183Cys (chr2-208243577-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005896.4(IDH1):c.548A>G(p.Tyr183Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,870 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0086 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 148 hom. )

Consequence

IDH1
NM_005896.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 3.19

Publications

34 publications found

Variant links:

COSMIC-nc: COSV61634138

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020163447).

BP6

Variant 2-208243577-T-C is Benign according to our data. Variant chr2-208243577-T-C is described in ClinVar as Benign. ClinVar VariationId is 134517.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0086 (1310/152314) while in subpopulation NFE AF = 0.0122 (831/68026). AF 95% confidence interval is 0.0115. There are 11 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1310 AD gene.

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.548A>G	p.Tyr183Cys	missense	Exon 6 of 10	NP_005887.2
IDH1	NM_001282386.1		c.548A>G	p.Tyr183Cys	missense	Exon 6 of 10	NP_001269315.1	O75874
IDH1	NM_001282387.1		c.548A>G	p.Tyr183Cys	missense	Exon 6 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.548A>G	p.Tyr183Cys	missense	Exon 6 of 10	ENSP00000260985.2	O75874
IDH1	ENST00000415913.5	TSL:1	c.548A>G	p.Tyr183Cys	missense	Exon 6 of 10	ENSP00000390265.1	O75874
IDH1	ENST00000446179.5	TSL:1	c.548A>G	p.Tyr183Cys	missense	Exon 6 of 10	ENSP00000410513.1	O75874

Frequencies

GnomAD3 genomes

AF:

0.00861

AC:

1310

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00972

AC:

2445

AN:

251436

AF XY:

0.00953

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0333

Gnomad NFE exome

AF:

0.0135

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0114

AC:

16706

AN:

1461556

Hom.:

148

Cov.:

AF XY:

0.0110

AC XY:

8031

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33478

American (AMR)

AF:

0.00248

AC:

111

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00302

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0334

AC:

1781

AN:

53402

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0127

AC:

14116

AN:

1111734

Other (OTH)

AF:

0.00870

AC:

525

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

807

1614

2421

3228

4035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00860

AC:

1310

AN:

152314

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41574

American (AMR)

AF:

0.00196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0330

AC:

350

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

831

AN:

68026

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00614

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0105

AC:

1280

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00872

EpiControl

AF:

0.0107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

IDH1-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.020

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.3

PhyloP100

3.2

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.75

MPC

0.81

ClinPred

0.13

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.92

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over