dbSNP rs767123432: TDO2:p.Ile165AspfsTer12 (chr4-155910082-C-CA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005651.4(TDO2):c.491dupA(p.Ile165AspfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,593,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as no classifications from unflagged records (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TDO2
NM_005651.4 frameshift

Scores

Not classified

Clinical Significance

no classifications from unflagged records no classifications from unflagged records P:1

Conservation

PhyloP100: 9.23

Publications

2 publications found

Variant links:

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)

TDO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005651.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDO2	NM_005651.4	MANE Select	c.491dupA	p.Ile165AspfsTer12	frameshift	Exon 6 of 12	NP_005642.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TDO2	ENST00000536354.3	TSL:1 MANE Select	c.491dupA	p.Ile165AspfsTer12	frameshift	Exon 6 of 12	ENSP00000444788.2
TDO2	ENST00000512584.5	TSL:1	n.2102-101dupA		intron	N/A
TDO2	ENST00000506072.5	TSL:3	c.170dupA	p.Ile58AspfsTer8	frameshift	Exon 8 of 8	ENSP00000423394.1

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000128

AC:

AN:

233672

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1442536

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

717934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32008

American (AMR)

AF:

0.00

AC:

AN:

40298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25742

East Asian (EAS)

AF:

0.00

AC:

AN:

36962

South Asian (SAS)

AF:

0.00

AC:

AN:

83718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000235

AC:

AN:

1105422

Other (OTH)

AF:

0.0000336

AC:

AN:

59498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150514

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40844

American (AMR)

AF:

0.00

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67750

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

LINK: link

Submissions by phenotype

Familial hypertryptophanemia

Pathogenic:1

Oct 04, 2017

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over