rs1553957997

Variant names:

• chr4-155908907-G-C
• rs1553957997
• NM_005651.4:c.324G>C

Variant summary

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

The NM_005651.4(TDO2):​c.324G>C​(p.Met108Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TDO2 NM_005651.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.52
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDO2	NM_005651.4	c.324G>C	p.Met108Ile	missense_variant	Exon 5 of 12	ENST00000536354.3	NP_005642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDO2	ENST00000536354.3	c.324G>C	p.Met108Ile	missense_variant	Exon 5 of 12	1	NM_005651.4	ENSP00000444788.2
TDO2	ENST00000512584.5	n.1994G>C		non_coding_transcript_exon_variant	Exon 2 of 9	1
TDO2	ENST00000506072.5	c.3G>C	p.Met1?	start_lost	Exon 7 of 8	3		ENSP00000423394.1
TDO2	ENST00000507590.5	c.3G>C	p.Met1?	start_lost	Exon 6 of 7	4		ENSP00000424384.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial hypertryptophanemia Pathogenic:1

Oct 04, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.0	.;.;M
PhyloP100		9.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.015	D;D;T
Polyphen		0.44	.;.;B
Vest4		0.85
MutPred		0.61		.;.;Loss of disorder (P = 0.0644);
MVP		0.15
MPC		0.20
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.70
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs1553957997; hg19: chr4-156830059;