Variant rs4290270 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_173353.4(TPH2):c.1125A>T(p.Ala375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,612,974 control chromosomes in the GnomAD database, including 305,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23593 hom., cov: 32)

Exomes 𝑓: 0.62 ( 282193 hom. )

Consequence

TPH2
NM_173353.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.959

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-72022455-A-T is Benign according to our data. Variant chr12-72022455-A-T is described in ClinVar as [Benign]. Clinvar id is 310388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.959 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4 linkuse as main transcript	c.1125A>T	p.Ala375=	synonymous_variant	9/11	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4 linkuse as main transcript	c.1125A>T	p.Ala375=	synonymous_variant	9/11	1	NM_173353.4	ENSP00000329093	P1	Q8IWU9-1

Frequencies

GnomAD3 genomes

AF:

0.548

AC:

83252

AN:

151848

Hom.:

23583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.410

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.609

Gnomad EAS

AF:

0.479

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.509

Gnomad MID

AF:

0.615

Gnomad NFE

AF:

0.639

Gnomad OTH

AF:

0.575

GnomAD3 exomes

AF:

0.571

AC:

143420

AN:

251170

Hom.:

41870

AF XY:

0.575

AC XY:

78021

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.405

Gnomad AMR exome

AF:

0.521

Gnomad ASJ exome

AF:

0.618

Gnomad EAS exome

AF:

0.480

Gnomad SAS exome

AF:

0.523

Gnomad FIN exome

AF:

0.526

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.601

GnomAD4 exome

AF:

0.618

AC:

903562

AN:

1461008

Hom.:

282193

Cov.:

AF XY:

0.617

AC XY:

448266

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.405

Gnomad4 AMR exome

AF:

0.521

Gnomad4 ASJ exome

AF:

0.619

Gnomad4 EAS exome

AF:

0.528

Gnomad4 SAS exome

AF:

0.520

Gnomad4 FIN exome

AF:

0.536

Gnomad4 NFE exome

AF:

0.645

Gnomad4 OTH exome

AF:

0.596

GnomAD4 genome

AF:

0.548

AC:

83295

AN:

151966

Hom.:

23593

Cov.:

AF XY:

0.542

AC XY:

40290

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.410

Gnomad4 AMR

AF:

0.554

Gnomad4 ASJ

AF:

0.609

Gnomad4 EAS

AF:

0.480

Gnomad4 SAS

AF:

0.519

Gnomad4 FIN

AF:

0.509

Gnomad4 NFE

AF:

0.639

Gnomad4 OTH

AF:

0.572

Alfa

AF:

0.616

Hom.:

9470

Bravo

AF:

0.546

Asia WGS

AF:

0.480

AC:

1667

AN:

3478

EpiCase

AF:

0.640

EpiControl

AF:

0.637

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

DANN

Benign

0.59

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

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