Genetic Variant TPH1:p.His78Tyr (chr11-18036028-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004179.3(TPH1):c.232C>T(p.His78Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,612,674 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 4 hom. )

Consequence

TPH1
NM_004179.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.69

Publications

5 publications found

Variant links:

Genes affected

TPH1 (HGNC:12008): (tryptophan hydroxylase 1) This gene encodes a member of the aromatic amino 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 have been associated with an elevated risk for a variety of diseases and disorders, including schizophrenia, somatic anxiety, anger-related traits, bipolar disorder, suicidal behavior, addictions, and others.[provided by RefSeq, Apr 2009]

TPH1 links:

ENSG00000302464 (HGNC:):

ENSG00000302464 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009954572).

BP6

Variant 11-18036028-G-A is Benign according to our data. Variant chr11-18036028-G-A is described in ClinVar as [Benign]. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH1	NM_004179.3 link	c.232C>T	p.His78Tyr	missense_variant	Exon 3 of 11	ENST00000682019.1	NP_004170.1	P17752-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH1	ENST00000682019.1 link	c.232C>T	p.His78Tyr	missense_variant	Exon 3 of 11		NM_004179.3	ENSP00000508368.1		P17752-1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000748

AC:

188

AN:

251222

AF XY:

0.000773

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000381

AC:

557

AN:

1460492

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

274

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33436

American (AMR)

AF:

0.000134

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

393

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5002

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

1111750

Other (OTH)

AF:

0.00128

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000375

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41448

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000869

Hom.:

Bravo

AF:

0.000510

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.027

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.010

T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.85

L;.

PhyloP100

6.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.031

D;.

Polyphen

0.16

B;.

Vest4

0.30

MVP

0.94

MPC

0.29

ClinPred

0.085

GERP RS

3.5

Varity_R

0.13

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over