10-1019620-G-T

Position:

• chr10-1019620-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033261.3(IDI2):​c.581C>A​(p.Thr194Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: IDI2 NM_033261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

Genes affected

IDI2 (HGNC:23487): (isopentenyl-diphosphate delta isomerase 2) The protein encoded by this gene catalyzes the conversion of isopentenyl diphosphate to dimethylallyl diphosphate, which is a precursor for the synthesis of cholesterol and other isoprenoids. This gene, which is a product of an ancestral gene duplication event, encodes a protein that may be involved in the aggregation of alpha-synuclein in the cerebral cortex of patients with Lewy body disease. In addition, segmental copy number gains in this locus have been associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2016]

GTPBP4 (HGNC:21535): (GTP binding protein 4) GTP-binding proteins are GTPases and function as molecular switches that can flip between two states: active, when GTP is bound, and inactive, when GDP is bound. 'Active' in this context usually means that the molecule acts as a signal to trigger other events in the cell. When an extracellular ligand binds to a G-protein-linked receptor, the receptor changes its conformation and switches on the trimeric G proteins that associate with it by causing them to eject their GDP and replace it with GTP. The switch is turned off when the G protein hydrolyzes its own bound GTP, converting it back to GDP. But before that occurs, the active protein has an opportunity to diffuse away from the receptor and deliver its message for a prolonged period to its downstream target. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDI2	NM_033261.3	c.581C>A	p.Thr194Asn	missense_variant	5/5	ENST00000277517.2	NP_150286.1
GTPBP4	NM_012341.3	c.*2393G>T		3_prime_UTR_variant	17/17	ENST00000360803.9	NP_036473.2
GTPBP4	XM_047424932.1	c.*2393G>T		3_prime_UTR_variant	17/17		XP_047280888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDI2	ENST00000277517.2	c.581C>A	p.Thr194Asn	missense_variant	5/5	1	NM_033261.3	ENSP00000277517.1
GTPBP4	ENST00000360803.9	c.*2393G>T		3_prime_UTR_variant	17/17	1	NM_012341.3	ENSP00000354040.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.581C>A (p.T194N) alteration is located in exon 5 (coding exon 4) of the IDI2 gene. This alteration results from a C to A substitution at nucleotide position 581, causing the threonine (T) at amino acid position 194 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.70		Loss of phosphorylation at T194 (P = 0.0909);
MVP		0.59
MPC		0.14
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.87
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs886824173; hg19: chr10-1065560;