4-155911563-A-C

Variant summary

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

The NM_005651.4(TDO2):c.685A>C(p.Asn229His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,600,778 control chromosomes in the GnomAD database, including 1,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (77 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1299 hom.)
• Consequence: TDO2 NM_005651.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.07

Genes affected

TDO2 (HGNC:11708): (tryptophan 2,3-dioxygenase) This gene encodes a heme enzyme that plays a critical role in tryptophan metabolism by catalyzing the first and rate-limiting step of the kynurenine pathway. Increased activity of the encoded protein and subsequent kynurenine production may also play a role in cancer through the suppression of antitumor immune responses, and single nucleotide polymorphisms in this gene may be associated with autism. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063344836).
• BP6: Variant 4-155911563-A-C is Benign according to our data. Variant chr4-155911563-A-C is described in ClinVar as [Benign]. Clinvar id is 3060816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0287 (4371/152220) while in subpopulation NFE AF= 0.0422 (2866/67972). AF 95% confidence interval is 0.0409. There are 77 homozygotes in gnomad4. There are 2095 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 4371 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDO2	NM_005651.4	c.685A>C	p.Asn229His	missense_variant	7/12	ENST00000536354.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDO2	ENST00000536354.3	c.685A>C	p.Asn229His	missense_variant	7/12	1	NM_005651.4	P1
TDO2	ENST00000512584.5	n.2195A>C		non_coding_transcript_exon_variant	4/9	1

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4371 AN: 152102 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0310 AC: 7564 AN: 244086 Hom.: 159 AF XY: 0.0317 AC XY: 4199 AN XY: 132534

Gnomad AFR exome AF: 0.00663

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.0446

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0398 AC: 57602 AN: 1448558 Hom.: 1299 Cov.: 32 AF XY: 0.0394 AC XY: 28364 AN XY: 720672

Gnomad4 AFR exome AF: 0.00647

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0530

Gnomad4 EAS exome AF: 0.0000773

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0359

GnomAD4 genome AF: 0.0287 AC: 4371 AN: 152220 Hom.: 77 Cov.: 32 AF XY: 0.0281 AC XY: 2095 AN XY: 74436

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0506

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0386 Hom.: 204

Bravo AF: 0.0262

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.0496 AC: 426

ExAC AF: 0.0305 AC: 3702

Asia WGS AF: 0.00434 AC: 15 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TDO2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.24
MPC		0.20
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.72
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs116105292; hg19: chr4-156832715;