8-39920102-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002164.6(IDO1):c.425C>T(p.Pro142Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,610,170 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: IDO1 NM_002164.6 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.18

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00745064).
• BP6: Variant 8-39920102-C-T is Benign according to our data. Variant chr8-39920102-C-T is described in ClinVar as [Benign]. Clinvar id is 786117.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0092 (1399/152120) while in subpopulation AFR AF= 0.031 (1287/41492). AF 95% confidence interval is 0.0296. There are 22 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDO1	NM_002164.6	c.425C>T	p.Pro142Leu	missense_variant, splice_region_variant	5/10	ENST00000518237.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDO1	ENST00000518237.6	c.425C>T	p.Pro142Leu	missense_variant, splice_region_variant	5/10	1	NM_002164.6	P1
	ENST00000517623.1	n.256-16081G>A		intron_variant, non_coding_transcript_variant		4
	ENST00000522970.1	n.256+533G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1398 AN: 152002 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00221 AC: 547 AN: 247614 Hom.: 7 AF XY: 0.00152 AC XY: 204 AN XY: 134324

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000997 AC: 1454 AN: 1458050 Hom.: 13 Cov.: 28 AF XY: 0.000830 AC XY: 602 AN XY: 725384

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000818

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00920 AC: 1399 AN: 152120 Hom.: 22 Cov.: 32 AF XY: 0.00894 AC XY: 665 AN XY: 74368

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00238 Hom.: 3

Bravo AF: 0.0109

ESP6500AA AF: 0.0270 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00262 AC: 317

Asia WGS AF: 0.00145 AC: 5 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;.;T
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.026	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.65, 0.64
MVP		0.71
MPC		0.041
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.40
gMVP		0.21

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: rs61753677; hg19: chr8-39777621;