8-39920101-C-A

Variant summary

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

The NM_002164.6(IDO1):c.424C>A(p.Pro142Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,610,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P142L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

IDO1
NM_002164.6 missense, splice_region

Scores

Splicing: ADA: 0.01353

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

IDO1 (HGNC:6059): (indoleamine 2,3-dioxygenase 1) This gene encodes indoleamine 2,3-dioxygenase (IDO) - a heme enzyme that catalyzes the first and rate-limiting step in tryptophan catabolism to N-formyl-kynurenine. This enzyme acts on multiple tryptophan substrates including D-tryptophan, L-tryptophan, 5-hydroxy-tryptophan, tryptamine, and serotonin. This enzyme is thought to play a role in a variety of pathophysiological processes such as antimicrobial and antitumor defense, neuropathology, immunoregulation, and antioxidant activity. Through its expression in dendritic cells, monocytes, and macrophages this enzyme modulates T-cell behavior by its peri-cellular catabolization of the essential amino acid tryptophan.[provided by RefSeq, Feb 2011]

IDO1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
IDO1	NM_002164.6 linkuse as main transcript	c.424C>A	p.Pro142Thr	missense_variant, splice_region_variant	5/10	ENST00000518237.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IDO1	ENST00000518237.6 linkuse as main transcript	c.424C>A	p.Pro142Thr	missense_variant, splice_region_variant	5/10	1	NM_002164.6	P1
	ENST00000517623.1 linkuse as main transcript	n.256-16080G>T		intron_variant, non_coding_transcript_variant		4
	ENST00000522970.1 linkuse as main transcript	n.256+534G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247794

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134406

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1458068

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

725358

show subpopulations

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:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.424C>A (p.P142T) alteration is located in exon 5 (coding exon 5) of the IDO1 gene. This alteration results from a C to A substitution at nucleotide position 424, causing the proline (P) at amino acid position 142 to be replaced by a threonine (T). 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

Benign

0.11

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

T;.;T

M_CAP

Benign

0.0098

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.45

MutationTaster

Benign

0.92

N;N

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.018

D;D;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.47, 0.47

MutPred

0.53

Loss of phosphorylation at T144 (P = 0.1164);Loss of phosphorylation at T144 (P = 0.1164);Loss of phosphorylation at T144 (P = 0.1164);

MVP

0.64

MPC

0.060

ClinPred

0.83

GERP RS

5.5

Varity_R

0.46

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.014

dbscSNV1_RF

Benign

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over