11-18036028-G-A

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

1
6
12

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]

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 CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar as Benign. Clinvar id is 781809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-18036028-G-A is described in CliVar 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
TPH1NM_004179.3 linkc.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
TPH1ENST00000682019.1 linkc.232C>T p.His78Tyr missense_variant Exon 3 of 11 NM_004179.3 ENSP00000508368.1 P17752-1

Frequencies

GnomAD3 genomes
AF:
0.000375
AC:
57
AN:
152182
Hom.:
0
Cov.:
32
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.:
4
Cov.:
30
AF XY:
0.000377
AC XY:
274
AN XY:
726610
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33436
American (AMR)
AF:
0.000134
AC:
6
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0150
AC:
393
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39632
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86206
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53324
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5002
European-Non Finnish (NFE)
AF:
0.0000702
AC:
78
AN:
1111750
Other (OTH)
AF:
0.00128
AC:
77
AN:
60298
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.461
Heterozygous variant carriers
0
30
60
90
120
150
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
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:
57
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000390
AC XY:
29
AN XY:
74332
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41448
American (AMR)
AF:
0.000196
AC:
3
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.0127
AC:
44
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68034
Other (OTH)
AF:
0.000478
AC:
1
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
3
Bravo
AF:
0.000510
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000519
AC:
63
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
T
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;.
Eigen
Benign
-0.027
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.85
D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.010
T;T
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Benign
0.85
L;.
PhyloP100
6.7
PrimateAI
Benign
0.31
T
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
T
GERP RS
3.5
Varity_R
0.13
gMVP
0.39
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs146455709; hg19: chr11-18057575; COSMIC: COSV51457149; API