rs34218846

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005896.4(IDH1):c.532G>A(p.Val178Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0534 in 1,611,912 control chromosomes in the GnomAD database, including 2,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V178V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 333 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2292 hom. )

Consequence

IDH1
NM_005896.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 7.68

Publications

60 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049711764).

BP6

Variant 2-208243593-C-T is Benign according to our data. Variant chr2-208243593-C-T is described in ClinVar as Benign. ClinVar VariationId is 134520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1	NM_005896.4 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10	ENST00000345146.7	NP_005887.2	O75874A0A024R3Y6
IDH1	NM_001282386.1 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10		NP_001269315.1	O75874A0A024R3Y6
IDH1	NM_001282387.1 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10		NP_001269316.1	O75874A0A024R3Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDH1	ENST00000345146.7 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10	1	NM_005896.4	ENSP00000260985.2	O75874
IDH1	ENST00000415913.5 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10	1		ENSP00000390265.1	O75874
IDH1	ENST00000446179.5 link	c.532G>A	p.Val178Ile	missense_variant	Exon 6 of 10	1		ENSP00000410513.1	O75874

Frequencies

GnomAD3 genomes

AF:

0.0595

AC:

9052

AN:

152124

Hom.:

333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0807

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0576

Gnomad ASJ

AF:

0.0928

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.0411

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0486

AC:

12225

AN:

251356

AF XY:

0.0492

show subpopulations

Gnomad AFR exome

AF:

0.0781

Gnomad AMR exome

AF:

0.0365

Gnomad ASJ exome

AF:

0.0871

Gnomad EAS exome

AF:

0.00658

Gnomad FIN exome

AF:

0.0240

Gnomad NFE exome

AF:

0.0551

Gnomad OTH exome

AF:

0.0567

GnomAD4 exome

AF:

0.0528

AC:

77066

AN:

1459670

Hom.:

2292

Cov.:

AF XY:

0.0527

AC XY:

38267

AN XY:

726298

show subpopulations

African (AFR)

AF:

0.0807

AC:

2698

AN:

33414

American (AMR)

AF:

0.0375

AC:

1675

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0819

AC:

2140

AN:

26114

East Asian (EAS)

AF:

0.0118

AC:

468

AN:

39680

South Asian (SAS)

AF:

0.0480

AC:

4142

AN:

86210

European-Finnish (FIN)

AF:

0.0276

AC:

1476

AN:

53388

Middle Eastern (MID)

AF:

0.0478

AC:

275

AN:

5758

European-Non Finnish (NFE)

AF:

0.0546

AC:

60577

AN:

1110086

Other (OTH)

AF:

0.0599

AC:

3615

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

3618

7236

10854

14472

18090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2272

4544

6816

9088

11360

<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:

0.0595

AC:

9056

AN:

152242

Hom.:

333

Cov.:

AF XY:

0.0578

AC XY:

4305

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0806

AC:

3349

AN:

41526

American (AMR)

AF:

0.0575

AC:

879

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0928

AC:

322

AN:

3468

East Asian (EAS)

AF:

0.0100

AC:

AN:

5176

South Asian (SAS)

AF:

0.0407

AC:

196

AN:

4818

European-Finnish (FIN)

AF:

0.0233

AC:

247

AN:

10610

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0568

AC:

3861

AN:

68034

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

434

869

1303

1738

2172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0560

Hom.:

880

Bravo

AF:

0.0618

TwinsUK

AF:

0.0591

AC:

219

ALSPAC

AF:

0.0560

AC:

216

ESP6500AA

AF:

0.0808

AC:

356

ESP6500EA

AF:

0.0531

AC:

457

ExAC

AF:

0.0500

AC:

6068

Asia WGS

AF:

0.0450

AC:

159

AN:

3478

EpiCase

AF:

0.0577

EpiControl

AF:

0.0600

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26599207) -

not specified

Benign:1Other:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.3

L;L;L

PhyloP100

7.7

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.85

N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.34

MPC

0.17

ClinPred

0.033

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.63

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over