chr8-39917921-A-C

Variant names:

• chr8-39917921-A-C
• rs1807200746
• NM_002164.6:c.134A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002164.6(IDO1):​c.134A>C​(p.His45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IDO1 NM_002164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4068987).

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.134A>C	p.His45Pro	missense	Exon 2 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.134A>C	p.His45Pro	missense	Exon 2 of 10	ENSP00000430950.1	P14902
	IDO1	ENST00000522495.5	TSL:5	c.134A>C	p.His45Pro	missense	Exon 4 of 12	ENSP00000430505.1	P14902
	IDO1	ENST00000519154.5	TSL:5	c.134A>C	p.His45Pro	missense	Exon 3 of 7	ENSP00000428716.1	A0A140T9Z2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461156 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726928

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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111528

Other (OTH) AF: 0.00 AC: 0 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Benign	0.060	T
Sift4G	Uncertain	0.020	D
Polyphen		0.78	P
Vest4		0.33
MutPred		0.61		Loss of ubiquitination at K44 (P = 0.0699)
MVP		0.52
MPC		0.12
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.70
Mutation Taster		=92/8	polymorphism

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: rs1807200746; hg19: chr8-39775440;