2-208237155-T-C

Variant names:

• chr2-208237155-T-C
• NM_005896.4:c.1169A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005896.4(IDH1):​c.1169A>G​(p.Asp390Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10	ENST00000345146.7	NP_005887.2
IDH1	NM_001282386.1	c.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10		NP_001269315.1
IDH1	NM_001282387.1	c.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10		NP_001269316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH1	ENST00000345146.7	c.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10	1	NM_005896.4	ENSP00000260985.2
IDH1	ENST00000415913.5	c.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10	1		ENSP00000390265.1
IDH1	ENST00000446179.5	c.1169A>G	p.Asp390Gly	missense_variant	Exon 10 of 10	1		ENSP00000410513.1
IDH1	ENST00000484575.1	n.631A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1452110 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D390G variant (also known as c.1169A>G), located in coding exon 8 of the IDH1 gene, results from an A to G substitution at nucleotide position 1169. The aspartic acid at codon 390 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.073	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.93	P;P;P
Vest4		0.69
MutPred		0.23		Loss of stability (P = 0.0631);Loss of stability (P = 0.0631);Loss of stability (P = 0.0631);
MVP		0.89
MPC		0.64
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-209101879;