8-39918130-C-A

Position:

• chr8-39918130-C-A

Variant summary

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

The NM_002164.6(IDO1):​c.226C>A​(p.Gln76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDO1 NM_002164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 (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=0.40551907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDO1	NM_002164.6	c.226C>A	p.Gln76Lys	missense_variant	3/10	ENST00000518237.6	NP_002155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDO1	ENST00000518237.6	c.226C>A	p.Gln76Lys	missense_variant	3/10	1	NM_002164.6	ENSP00000430950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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 23, 2024

The c.226C>A (p.Q76K) alteration is located in exon 3 (coding exon 3) of the IDO1 gene. This alteration results from a C to A substitution at nucleotide position 226, causing the glutamine (Q) at amino acid position 76 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.022	T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T;T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.1	.;.;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.4	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.56	T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		1.0	.;.;D;D
Vest4		0.32, 0.33
MutPred		0.67		Gain of methylation at Q76 (P = 0.0278);Gain of methylation at Q76 (P = 0.0278);Gain of methylation at Q76 (P = 0.0278);Gain of methylation at Q76 (P = 0.0278);
MVP		0.45
MPC		0.29
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.54
gMVP		0.43

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: rs1173666738; hg19: chr8-39775649;