8-39925220-T-C

Position:

• chr8-39925220-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002164.6(IDO1):​c.708-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,574,580 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: IDO1 NM_002164.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003295
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.213

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-39925220-T-C is Benign according to our data. Variant chr8-39925220-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 733967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDO1	NM_002164.6	c.708-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000518237.6	NP_002155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDO1	ENST00000518237.6	c.708-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002164.6	ENSP00000430950	P1
	ENST00000517623.1	n.256-21199A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00191 AC: 413 AN: 216322 Hom.: 1 AF XY: 0.00167 AC XY: 197 AN XY: 117920

Gnomad AFR exome AF: 0.00849

Gnomad AMR exome AF: 0.00473

Gnomad ASJ exome AF: 0.00710

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00112 AC: 1590 AN: 1422326 Hom.: 5 Cov.: 31 AF XY: 0.00110 AC XY: 775 AN XY: 705348

Gnomad4 AFR exome AF: 0.00734

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000755

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74452

Gnomad4 AFR AF: 0.00775

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00488

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.9
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0060
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

Publications

LitVar

Other links and lift over

dbSNP: rs118036045; hg19: chr8-39782739;