Variant 12-71944686-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_173353.4(TPH2):c.540A>G(p.Pro180Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,416 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 9 hom. )

Consequence

TPH2
NM_173353.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0001197

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.235

Variant links:

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]

TPH2 links:

TPH2 (HGNC:):

TPH2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-71944686-A-G is Benign according to our data. Variant chr12-71944686-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 310383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.235 with no splicing effect.

BS2

High AC in GnomAd4 at 325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4 linkuse as main transcript	c.540A>G	p.Pro180Pro	splice_region_variant, synonymous_variant	4/11	ENST00000333850.4	NP_775489.2	Q8IWU9-1
TPH2	XR_001748575.2 linkuse as main transcript	n.682A>G		splice_region_variant, non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4 linkuse as main transcript	c.540A>G	p.Pro180Pro	splice_region_variant, synonymous_variant	4/11	1	NM_173353.4	ENSP00000329093.3		Q8IWU9-1
TPH2	ENST00000546576.1 linkuse as main transcript	n.550A>G		splice_region_variant, non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00279

AC:

700

AN:

250738

Hom.:

AF XY:

0.00268

AC XY:

363

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00197

AC:

2880

AN:

1461130

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1352

AN XY:

726890

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.00169

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00213

AC:

325

AN:

152286

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

194

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0173

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.000767

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination 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

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.054

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over