8-39918922-G-C

Variant names:

• chr8-39918922-G-C
• rs767023043
• NM_002164.6:c.411G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002164.6(IDO1):​c.411G>C​(p.Lys137Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,416,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IDO1 NM_002164.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 0 publications found

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]

ENSG00000253939 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002164.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDO1	NM_002164.6	MANE Select	c.411G>C	p.Lys137Asn	missense	Exon 4 of 10	NP_002155.1	P14902

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDO1	ENST00000518237.6	TSL:1 MANE Select	c.411G>C	p.Lys137Asn	missense	Exon 4 of 10	ENSP00000430950.1	P14902
	IDO1	ENST00000522495.5	TSL:5	c.411G>C	p.Lys137Asn	missense	Exon 6 of 12	ENSP00000430505.1	P14902
	IDO1	ENST00000519154.5	TSL:5	c.411G>C	p.Lys137Asn	missense	Exon 5 of 7	ENSP00000428716.1	A0A140T9Z2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1416866 Hom.: 0 Cov.: 26 AF XY: 0.00000424 AC XY: 3 AN XY: 707674

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000923 AC: 3 AN: 32502

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39488

South Asian (SAS) AF: 0.00 AC: 0 AN: 85370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1071016

Other (OTH) AF: 0.00 AC: 0 AN: 58932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0132501), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.54		Loss of methylation at K137 (P = 0.0092)
MVP		0.63
MPC		0.28
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.31
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs767023043; hg19: chr8-39776441;