rs11554137

Positions:

• chr2-208248468-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005896.4(IDH1):​c.315C>T​(p.Gly105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,613,868 control chromosomes in the GnomAD database, including 2,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G105G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (442 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2392 hom.)
• Consequence: IDH1 NM_005896.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-208248468-G-A is Benign according to our data. Variant chr2-208248468-G-A is described in ClinVar as [Benign]. Clinvar id is 402961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH1	NM_005896.4	c.315C>T	p.Gly105=	synonymous_variant	4/10	ENST00000345146.7
IDH1	NM_001282386.1	c.315C>T	p.Gly105=	synonymous_variant	4/10
IDH1	NM_001282387.1	c.315C>T	p.Gly105=	synonymous_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH1	ENST00000345146.7	c.315C>T	p.Gly105=	synonymous_variant	4/10	1	NM_005896.4	P1

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10107 AN: 152062 Hom.: 441 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0656

GnomAD3 exomes AF: 0.0506 AC: 12716 AN: 251452 Hom.: 418 AF XY: 0.0506 AC XY: 6881 AN XY: 135906

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0870

Gnomad EAS exome AF: 0.00674

Gnomad SAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0540 AC: 78889 AN: 1461688 Hom.: 2392 Cov.: 33 AF XY: 0.0537 AC XY: 39059 AN XY: 727140

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0390

Gnomad4 ASJ exome AF: 0.0822

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0484

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0551

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome AF: 0.0665 AC: 10120 AN: 152180 Hom.: 442 Cov.: 32 AF XY: 0.0648 AC XY: 4819 AN XY: 74412

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0600

Gnomad4 ASJ AF: 0.0930

Gnomad4 EAS AF: 0.0101

Gnomad4 SAS AF: 0.0411

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0568

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0639 Hom.: 156

Bravo AF: 0.0693

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.0579

EpiControl AF: 0.0603

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.8
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11554137; hg19: chr2-209113192; COSMIC: COSV61616039; COSMIC: COSV61616039;