8-39920111-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002164.6(IDO1):c.434A>G(p.Tyr145Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDO1 NM_002164.6 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDO1	NM_002164.6	c.434A>G	p.Tyr145Cys	missense_variant	5/10	ENST00000518237.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDO1	ENST00000518237.6	c.434A>G	p.Tyr145Cys	missense_variant	5/10	1	NM_002164.6	P1
	ENST00000517623.1	n.256-16090T>C		intron_variant, non_coding_transcript_variant		4
	ENST00000522970.1	n.256+524T>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

Feb 14, 2023

The c.434A>G (p.Y145C) 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 434, causing the tyrosine (Y) at amino acid position 145 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.64	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.093	T;T;T
Sift4G	Uncertain	0.040	D;T;T
Polyphen		1.0	.;D;D
Vest4		0.86
MutPred		0.67		Loss of phosphorylation at Y145 (P = 0.0315);Loss of phosphorylation at Y145 (P = 0.0315);Loss of phosphorylation at Y145 (P = 0.0315);
MVP		0.68
MPC		0.27
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1214877109; hg19: chr8-39777630;