Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005896.4(IDH1):c.315C>T(p.Gly105Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,613,868 control chromosomes in the GnomAD database, including 2,834 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. G105G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.067 ( 442 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2392 hom. )

Consequence

IDH1
NM_005896.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.35

Publications

91 publications found

Variant links:

COSMIC-nc: COSV61616039

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-208248468-G-A is Benign according to our data. Variant chr2-208248468-G-A is described in ClinVar as Benign. ClinVar VariationId is 402961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.35 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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
IDH1	NM_005896.4	MANE Select	c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	NP_005887.2
IDH1	NM_001282386.1		c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	NP_001269315.1
IDH1	NM_001282387.1		c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	NP_001269316.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDH1	ENST00000345146.7	TSL:1 MANE Select	c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	ENSP00000260985.2
IDH1	ENST00000415913.5	TSL:1	c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	ENSP00000390265.1
IDH1	ENST00000446179.5	TSL:1	c.315C>T	p.Gly105Gly	synonymous	Exon 4 of 10	ENSP00000410513.1

Frequencies

GnomAD3 genomes

AF:

0.0665

AC:

10107

AN:

152062

Hom.:

441

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0600

Gnomad ASJ

AF:

0.0930

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.0235

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0656

GnomAD2 exomes

AF:

0.0506

AC:

12716

AN:

251452

AF XY:

0.0506

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.0377

Gnomad ASJ exome

AF:

0.0870

Gnomad EAS exome

AF:

0.00674

Gnomad FIN exome

AF:

0.0241

Gnomad NFE exome

AF:

0.0552

Gnomad OTH exome

AF:

0.0582

GnomAD4 exome

AF:

0.0540

AC:

78889

AN:

1461688

Hom.:

2392

Cov.:

AF XY:

0.0537

AC XY:

39059

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.106

AC:

3543

AN:

33478

American (AMR)

AF:

0.0390

AC:

1743

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0822

AC:

2149

AN:

26136

East Asian (EAS)

AF:

0.0119

AC:

471

AN:

39698

South Asian (SAS)

AF:

0.0484

AC:

4178

AN:

86250

European-Finnish (FIN)

AF:

0.0277

AC:

1479

AN:

53420

Middle Eastern (MID)

AF:

0.0498

AC:

287

AN:

5768

European-Non Finnish (NFE)

AF:

0.0551

AC:

61301

AN:

1111822

Other (OTH)

AF:

0.0619

AC:

3738

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

4051

8102

12153

16204

20255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2324

4648

6972

9296

11620

<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:

0.0665

AC:

10120

AN:

152180

Hom.:

442

Cov.:

AF XY:

0.0648

AC XY:

4819

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.105

AC:

4359

AN:

41512

American (AMR)

AF:

0.0600

AC:

916

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0930

AC:

323

AN:

3472

East Asian (EAS)

AF:

0.0101

AC:

AN:

5170

South Asian (SAS)

AF:

0.0411

AC:

198

AN:

4820

European-Finnish (FIN)

AF:

0.0235

AC:

249

AN:

10604

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0568

AC:

3863

AN:

68010

Other (OTH)

AF:

0.0649

AC:

137

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

470

940

1411

1881

2351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0639

Hom.:

156

Bravo

AF:

0.0693

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

EpiCase

AF:

0.0579

EpiControl

AF:

0.0603

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.8

(source)

DANN

Benign

0.68

PhyloP100

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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.

rs11554137

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over