2-208248572-C-A

Variant names:

• chr2-208248572-C-A
• rs73070954
• NM_005896.4:c.211G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005896.4(IDH1):​c.211G>T​(p.Val71Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V71I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.845
• Publications: 0 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 syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1	NM_005896.4	c.211G>T	p.Val71Phe	missense_variant	Exon 4 of 10	ENST00000345146.7	NP_005887.2
IDH1	NM_001282386.1	c.211G>T	p.Val71Phe	missense_variant	Exon 4 of 10		NP_001269315.1
IDH1	NM_001282387.1	c.211G>T	p.Val71Phe	missense_variant	Exon 4 of 10		NP_001269316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH1	ENST00000345146.7	c.211G>T	p.Val71Phe	missense_variant	Exon 4 of 10	1	NM_005896.4	ENSP00000260985.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;D;D;.;D
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.91	.;.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.6	H;H;H;.;.
PhyloP100		0.84
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.044	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;.
Polyphen		0.016	B;B;B;.;.
Vest4		0.79
MutPred		0.72		Loss of glycosylation at T75 (P = 0.1599);Loss of glycosylation at T75 (P = 0.1599);Loss of glycosylation at T75 (P = 0.1599);Loss of glycosylation at T75 (P = 0.1599);Loss of glycosylation at T75 (P = 0.1599);
MVP		0.73
MPC		0.28
ClinPred		0.98	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.95
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs73070954; hg19: chr2-209113296;