NM_194294.5:c.1038T>A

Variant names:

• chr8-40015416-T-A
• rs4503083
• NM_194294.5:c.1038T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_194294.5(IDO2):​c.1038T>A​(p.Tyr346*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,613,680 control chromosomes in the GnomAD database, including 35,935 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3180 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32755 hom.)
• Consequence: IDO2 NM_194294.5 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.108
• Publications: 48 publications found

Genes affected

IDO2 (HGNC:27269): (indoleamine 2,3-dioxygenase 2) Along with the enzymes encoded by the INDO (MIM 147435) and TDO2 (MIM 191070) genes, the enzyme encoded by the INDOL1 gene metabolizes tryptophan in the kynurenine pathway (Ball et al., 2007 [PubMed 17499941]).[supplied by OMIM, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-40015416-T-A is Benign according to our data. Variant chr8-40015416-T-A is described in ClinVar as [Benign]. Clinvar id is 1229251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDO2	NM_194294.5	c.1038T>A	p.Tyr346*	stop_gained	Exon 11 of 11	ENST00000502986.4	NP_919270.3
IDO2	NM_001395206.1	c.1038T>A	p.Tyr346*	stop_gained	Exon 10 of 10		NP_001382135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDO2	ENST00000502986.4	c.1038T>A	p.Tyr346*	stop_gained	Exon 11 of 11	5	NM_194294.5	ENSP00000443432.2
IDO2	ENST00000343295.8	n.3289T>A		non_coding_transcript_exon_variant	Exon 11 of 11	2
IDO2	ENST00000418094.1	n.665T>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29890 AN: 151990 Hom.: 3179 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.227 AC: 56546 AN: 248808 AF XY: 0.227

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.208 AC: 304115 AN: 1461576 Hom.: 32755 Cov.: 49 AF XY: 0.209 AC XY: 152000 AN XY: 727050

African (AFR) AF: 0.124 AC: 4143 AN: 33478

American (AMR) AF: 0.278 AC: 12418 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4171 AN: 26134

East Asian (EAS) AF: 0.374 AC: 14839 AN: 39690

South Asian (SAS) AF: 0.231 AC: 19962 AN: 86254

European-Finnish (FIN) AF: 0.205 AC: 10967 AN: 53396

Middle Eastern (MID) AF: 0.235 AC: 1353 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223968 AN: 1111790

Other (OTH) AF: 0.204 AC: 12294 AN: 60370

GnomAD4 genome AF: 0.197 AC: 29895 AN: 152104 Hom.: 3180 Cov.: 32 AF XY: 0.200 AC XY: 14865 AN XY: 74360

African (AFR) AF: 0.125 AC: 5174 AN: 41508

American (AMR) AF: 0.265 AC: 4046 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3472

East Asian (EAS) AF: 0.361 AC: 1853 AN: 5138

South Asian (SAS) AF: 0.227 AC: 1096 AN: 4820

European-Finnish (FIN) AF: 0.199 AC: 2111 AN: 10598

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14194 AN: 67980

Other (OTH) AF: 0.214 AC: 451 AN: 2112

Alfa AF: 0.199 Hom.: 987

Bravo AF: 0.200

TwinsUK AF: 0.201 AC: 744

ALSPAC AF: 0.213 AC: 821

ESP6500AA AF: 0.110 AC: 458

ESP6500EA AF: 0.207 AC: 1743

ExAC AF: 0.225 AC: 27248

Asia WGS AF: 0.279 AC: 969 AN: 3478

EpiCase AF: 0.207

EpiControl AF: 0.213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25541686, 17671174) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		0.11
Vest4		0.89
GERP RS		-2.2
Mutation Taster		=184/16	polymorphism (auto)

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: rs4503083; hg19: chr8-39872935; COSMIC: COSV58423710;