chr8-39913932-G-A

Position:

• chr8-39913932-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000518237.6(IDO1):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,569,164 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0099 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: IDO1 ENST00000518237.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.215

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028638542).
• BP6: Variant 8-39913932-G-A is Benign according to our data. Variant chr8-39913932-G-A is described in ClinVar as [Benign]. Clinvar id is 786116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00994 (1514/152288) while in subpopulation AFR AF= 0.0337 (1400/41550). AF 95% confidence interval is 0.0322. There are 24 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDO1	NM_002164.6	c.10G>A	p.Ala4Thr	missense_variant	1/10	ENST00000518237.6	NP_002155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDO1	ENST00000518237.6	c.10G>A	p.Ala4Thr	missense_variant	1/10	1	NM_002164.6	ENSP00000430950	P1
	ENST00000517623.1	n.256-9911C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00991 AC: 1508 AN: 152170 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

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: 0.0000735

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00217 AC: 400 AN: 184434 Hom.: 6 AF XY: 0.00158 AC XY: 154 AN XY: 97720

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000255

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00106 AC: 1507 AN: 1416876 Hom.: 15 Cov.: 29 AF XY: 0.000915 AC XY: 641 AN XY: 700414

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000165

Gnomad4 OTH exome AF: 0.00266

GnomAD4 genome AF: 0.00994 AC: 1514 AN: 152288 Hom.: 24 Cov.: 33 AF XY: 0.00968 AC XY: 721 AN XY: 74482

Gnomad4 AFR AF: 0.0337

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00146 Hom.: 4

Bravo AF: 0.0117

ESP6500AA AF: 0.0285 AC: 111

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00220 AC: 262

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.0
DANN	Benign	0.88
DEOGEN2	Benign	0.0064	T;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.56	T;T;.;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.28	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.94	T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.047	.;.;B;.;B
Vest4		0.015, 0.0050
MVP		0.13
MPC		0.039
ClinPred		0.00093	T
GERP RS		-0.40
Varity_R		0.030
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35059413; hg19: chr8-39771451; COSMIC: COSV99503297; COSMIC: COSV99503297;