8-39920107-A-G

Position:

• chr8-39920107-A-G

Variant summary

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

The ENST00000518237.6(IDO1):​c.430A>G​(p.Thr144Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDO1 ENST00000518237.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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]

(HGNC:):

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=0.3354047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDO1	NM_002164.6	c.430A>G	p.Thr144Ala	missense_variant	5/10	ENST00000518237.6	NP_002155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDO1	ENST00000518237.6	c.430A>G	p.Thr144Ala	missense_variant	5/10	1	NM_002164.6	ENSP00000430950	P1
	ENST00000517623.1	n.256-16086T>C		intron_variant, non_coding_transcript_variant		4
	ENST00000522970.1	n.256+528T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

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

Apr 08, 2024

The c.430A>G (p.T144A) alteration is located in exon 5 (coding exon 5) of the IDO1 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the threonine (T) at amino acid position 144 to be replaced by an alanine (A). 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	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.17	.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.022
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T;.;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	.;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.010	.;B;B
Vest4		0.45, 0.45
MutPred		0.54		Loss of phosphorylation at T144 (P = 0.0579);Loss of phosphorylation at T144 (P = 0.0579);Loss of phosphorylation at T144 (P = 0.0579);
MVP		0.41
MPC		0.035
ClinPred		0.40	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1807249812; hg19: chr8-39777626;