rs34115267

chr12-71941584-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173353.4(TPH2):c.106C>G(p.Leu36Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,613,698 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L36P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: TPH2 NM_173353.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009272
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.281

Genes affected

TPH2 (HGNC:20692): (tryptophan hydroxylase 2) This gene encodes a member of the pterin-dependent aromatic acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene may be associated with psychiatric diseases such as bipolar affective disorder and major depression. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028747022).
• BP6: Variant 12-71941584-C-G is Benign according to our data. Variant chr12-71941584-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 713133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 677 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.106C>G	p.Leu36Val	missense_variant, splice_region_variant	2/11	ENST00000333850.4
TPH2	XR_001748575.2	n.248C>G		splice_region_variant, non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.106C>G	p.Leu36Val	missense_variant, splice_region_variant	2/11	1	NM_173353.4	P1
TPH2	ENST00000546576.1	n.116C>G		splice_region_variant, non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 677 AN: 152056 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00121 AC: 304 AN: 250724 Hom.: 1 AF XY: 0.000841 AC XY: 114 AN XY: 135522

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000430 AC: 628 AN: 1461524 Hom.: 5 Cov.: 31 AF XY: 0.000362 AC XY: 263 AN XY: 727064

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.00446 AC: 678 AN: 152174 Hom.: 6 Cov.: 32 AF XY: 0.00441 AC XY: 328 AN XY: 74406

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000562 Hom.: 0

Bravo AF: 0.00512

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0029	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.26
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.083
MVP		0.16
MPC		0.33
ClinPred		0.0012	T
GERP RS		0.70
Varity_R		0.044
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00093
dbscSNV1_RF	Benign	0.19
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

LitVar

Other links and lift over

dbSNP: rs34115267; hg19: chr12-72335364; COSMIC: COSV61592987;