rs121913499
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_005896.4(IDH1):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132G) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IDH1
NM_005896.4 missense
NM_005896.4 missense
Scores
11
7
Clinical Significance
Conservation
PhyloP100: 7.10
Publications
1100 publications found
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 syndromeInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-208248388-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 156444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-208248389-G-A is Pathogenic according to our data. Variant chr2-208248389-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDH1 | NM_005896.4 | MANE Select | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | NP_005887.2 | ||
| IDH1 | NM_001282386.1 | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | NP_001269315.1 | |||
| IDH1 | NM_001282387.1 | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | NP_001269316.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDH1 | ENST00000345146.7 | TSL:1 MANE Select | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | ENSP00000260985.2 | ||
| IDH1 | ENST00000415913.5 | TSL:1 | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | ENSP00000390265.1 | ||
| IDH1 | ENST00000446179.5 | TSL:1 | c.394C>T | p.Arg132Cys | missense | Exon 4 of 10 | ENSP00000410513.1 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151438Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151438
Hom.:
Cov.:
32
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GnomAD2 exomes AF: 0.00 AC: 0AN: 251292 AF XY: 0.00
GnomAD2 exomes
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727162
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461688
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727162
African (AFR)
AF:
AC:
0
AN:
33472
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86246
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111854
Other (OTH)
AF:
AC:
0
AN:
60380
GnomAD4 genome 0.00000660 AC: 1AN: 151438Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73904 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
151438
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
73904
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41230
American (AMR)
AF:
AC:
0
AN:
15172
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5178
South Asian (SAS)
AF:
AC:
0
AN:
4804
European-Finnish (FIN)
AF:
AC:
0
AN:
10340
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67936
Other (OTH)
AF:
AC:
0
AN:
2084
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
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Allele balance
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ClinVar
ClinVar submissions as Germline
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts