4-155910292-G-T

Variant names:

• chr4-155910292-G-T
• rs10517626
• NM_005651.4:c.618+81G>T

Variant summary

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

The NM_005651.4(TDO2):​c.618+81G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,101,874 control chromosomes in the GnomAD database, including 11,038 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 0.18 (3281 hom., cov: 30)
  • Exomes 𝑓: 0.12 (7757 hom.)
• Consequence: TDO2 NM_005651.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728
• Publications: 11 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDO2	NM_005651.4	c.618+81G>T		intron_variant	Intron 6 of 11	ENST00000536354.3	NP_005642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDO2	ENST00000536354.3	c.618+81G>T		intron_variant	Intron 6 of 11	1	NM_005651.4	ENSP00000444788.2
TDO2	ENST00000512584.5	n.2128+81G>T		intron_variant	Intron 3 of 8	1
TDO2	ENST00000506072.5	c.*182G>T		downstream_gene_variant		3		ENSP00000423394.1
TDO2	ENST00000507590.5	c.*230G>T		downstream_gene_variant		4		ENSP00000424384.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27321 AN: 151678 Hom.: 3275 Cov.: 30

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.117 AC: 111246 AN: 950078 Hom.: 7757 AF XY: 0.120 AC XY: 57913 AN XY: 483760

African (AFR) AF: 0.339 AC: 6320 AN: 18622

American (AMR) AF: 0.152 AC: 2731 AN: 18012

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 2466 AN: 19376

East Asian (EAS) AF: 0.164 AC: 4852 AN: 29530

South Asian (SAS) AF: 0.213 AC: 11768 AN: 55150

European-Finnish (FIN) AF: 0.131 AC: 5883 AN: 44968

Middle Eastern (MID) AF: 0.183 AC: 548 AN: 2990

European-Non Finnish (NFE) AF: 0.0986 AC: 70932 AN: 719562

Other (OTH) AF: 0.137 AC: 5746 AN: 41868

GnomAD4 genome AF: 0.180 AC: 27357 AN: 151796 Hom.: 3281 Cov.: 30 AF XY: 0.181 AC XY: 13445 AN XY: 74184

African (AFR) AF: 0.331 AC: 13707 AN: 41390

American (AMR) AF: 0.159 AC: 2423 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3460

East Asian (EAS) AF: 0.124 AC: 633 AN: 5114

South Asian (SAS) AF: 0.225 AC: 1082 AN: 4814

European-Finnish (FIN) AF: 0.131 AC: 1379 AN: 10520

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.105 AC: 7135 AN: 67936

Other (OTH) AF: 0.176 AC: 370 AN: 2104

Alfa AF: 0.112 Hom.: 1045

Bravo AF: 0.186

Asia WGS AF: 0.224 AC: 777 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.010
DANN	Benign	0.31
PhyloP100		-0.73
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: rs10517626; hg19: chr4-156831444;