rs34599179

chr2-208243577-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 3.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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 id is 134517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208243577-T-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IDH1	NM_005896.4 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10	ENST00000345146.7
IDH1	NM_001282386.1 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10
IDH1	NM_001282387.1 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IDH1	ENST00000345146.7 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10	1	NM_005896.4	P1
IDH1	ENST00000415913.5 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10	1		P1
IDH1	ENST00000446179.5 linkuse as main transcript	c.548A>G	p.Tyr183Cys	missense_variant	6/10	1		P1

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

GnomAD3 exomes

AF:

0.00972

AC:

2445

AN:

251436

Hom.:

AF XY:

0.00953

AC XY:

1295

AN XY:

135888

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 SAS exome

AF:

0.000196

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

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00302

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0334

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.00870

GnomAD4 genome

AF:

0.00860

AC:

1310

AN:

152314

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0330

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00711

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

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

IDH1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

IDH1: BS1, BS2 -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.3

H;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over