Genetic Variant IDH1:c.-217C>A (chr2-208255534-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000451391.5(IDH1):c.-217C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,152 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2817 hom., cov: 33)

Exomes 𝑓: 0.14 ( 0 hom. )

Consequence

IDH1
ENST00000451391.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850

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:

IDH1-AS1 (HGNC:40292): (IDH1 antisense RNA 1)

IDH1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1-AS1	NR_046452.1 link	n.199+103G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
IDH1	ENST00000417583.5 link	c.-217C>A	5_prime_UTR_variant	Exon 1 of 5	4	ENSP00000409045.1	C9JLU6
IDH1	ENST00000451391.5 link	c.-217C>A	5_prime_UTR_variant	Exon 2 of 6	3	ENSP00000396787.1	C9JJE5
IDH1-AS1	ENST00000448588.1 link	n.135G>T	non_coding_transcript_exon_variant	Exon 1 of 2	3
IDH1-AS1	ENST00000440574.2 link	n.218+103G>T	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25725

AN:

151984

Hom.:

2813

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0579

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.486

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.198

GnomAD4 exome

AF:

0.140

AC:

AN:

Hom.:

Cov.:

AF XY:

0.143

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.136

GnomAD4 genome

AF:

0.169

AC:

25737

AN:

152102

Hom.:

2817

Cov.:

AF XY:

0.171

AC XY:

12743

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0579

Gnomad4 AMR

AF:

0.186

Gnomad4 ASJ

AF:

0.228

Gnomad4 EAS

AF:

0.487

Gnomad4 SAS

AF:

0.233

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.200

Gnomad4 OTH

AF:

0.197

Alfa

AF:

0.192

Hom.:

3092

Bravo

AF:

0.170

Asia WGS

AF:

0.321

AC:

1116

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.3

DANN

Benign

0.80

Splicing

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over