4-155908671-A-C

Variant names:

• chr4-155908671-A-C
• rs2271537
• NM_005651.4:c.304-216A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005651.4(TDO2):​c.304-216A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,062 control chromosomes in the GnomAD database, including 15,755 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (15755 hom., cov: 32)
• Consequence: TDO2 NM_005651.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 8 publications found

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]

TDO2 Gene-Disease associations (from GenCC):

• familial hypertryptophanemia

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDO2	NM_005651.4	c.304-216A>C		intron_variant	Intron 4 of 11	ENST00000536354.3	NP_005642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDO2	ENST00000536354.3	c.304-216A>C		intron_variant	Intron 4 of 11	1	NM_005651.4	ENSP00000444788.2
TDO2	ENST00000512584.5	n.1974-216A>C		intron_variant	Intron 1 of 8	1
TDO2	ENST00000506072.5	c.-18-216A>C		intron_variant	Intron 6 of 7	3		ENSP00000423394.1
TDO2	ENST00000507590.5	c.-18-216A>C		intron_variant	Intron 5 of 6	4		ENSP00000424384.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62278 AN: 151944 Hom.: 15748 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.438

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.410 AC: 62291 AN: 152062 Hom.: 15755 Cov.: 32 AF XY: 0.416 AC XY: 30884 AN XY: 74322

African (AFR) AF: 0.105 AC: 4362 AN: 41498

American (AMR) AF: 0.491 AC: 7501 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1414 AN: 3470

East Asian (EAS) AF: 0.728 AC: 3758 AN: 5164

South Asian (SAS) AF: 0.431 AC: 2077 AN: 4818

European-Finnish (FIN) AF: 0.598 AC: 6303 AN: 10544

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35441 AN: 67966

Other (OTH) AF: 0.438 AC: 925 AN: 2112

Alfa AF: 0.453 Hom.: 6243

Bravo AF: 0.392

Asia WGS AF: 0.523 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.77
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs2271537; hg19: chr4-156829823;