2-208237145-A-T

Variant names:

• chr2-208237145-A-T
• NM_005896.4:c.1179T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BS2_Supporting

The NM_005896.4(IDH1):​c.1179T>A​(p.Asn393Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N393S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH1	NM_005896.4	MANE Select	c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	NP_005887.2
	IDH1	NM_001282386.1		c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	NP_001269315.1	O75874
	IDH1	NM_001282387.1		c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	NP_001269316.1	A0A024R3Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH1	ENST00000345146.7	TSL:1 MANE Select	c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	ENSP00000260985.2	O75874
	IDH1	ENST00000415913.5	TSL:1	c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	ENSP00000390265.1	O75874
	IDH1	ENST00000446179.5	TSL:1	c.1179T>A	p.Asn393Lys	missense	Exon 10 of 10	ENSP00000410513.1	O75874

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456268 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724804

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107358

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.084	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.031	D
Polyphen		0.87	P
Vest4		0.56
MutPred		0.40		Gain of ubiquitination at N393 (P = 0.023)
MVP		0.90
MPC		0.47
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.95
Mutation Taster		=56/44	polymorphism

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

hg19: chr2-209101869;