rs760963029

Variant names:

• chr2-208237169-A-C
• rs760963029
• NM_005896.4:c.1155T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-208237169-A-C
• chr2-208237169-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005896.4(IDH1):​c.1155T>G​(p.Asn385Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IDH1 NM_005896.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002230
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3971688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1	NM_005896.4	c.1155T>G	p.Asn385Lys	missense_variant, splice_region_variant	Exon 10 of 10	ENST00000345146.7	NP_005887.2
IDH1	NM_001282386.1	c.1155T>G	p.Asn385Lys	missense_variant, splice_region_variant	Exon 10 of 10		NP_001269315.1
IDH1	NM_001282387.1	c.1155T>G	p.Asn385Lys	missense_variant, splice_region_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.1155T>G	p.Asn385Lys	missense_variant, splice_region_variant	Exon 10 of 10	1	NM_005896.4	ENSP00000260985.2
IDH1	ENST00000415913.5	c.1155T>G	p.Asn385Lys	missense_variant, splice_region_variant	Exon 10 of 10	1		ENSP00000390265.1
IDH1	ENST00000446179.5	c.1155T>G	p.Asn385Lys	missense_variant, splice_region_variant	Exon 10 of 10	1		ENSP00000410513.1
IDH1	ENST00000484575.1	n.617T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437494 Hom.: 0 Cov.: 24 AF XY: 0.00000279 AC XY: 2 AN XY: 716600

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: 0.00000183

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.065
DANN	Benign	0.60
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	.;.;D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.61	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.66
MutPred		0.46		Gain of methylation at N385 (P = 0.0192);Gain of methylation at N385 (P = 0.0192);Gain of methylation at N385 (P = 0.0192);
MVP		0.57
MPC		0.21
ClinPred		0.31	T
GERP RS		-10
Varity_R		0.58
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.14
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

Publications

LitVar

Other links and lift over

dbSNP: rs760963029; hg19: chr2-209101893;