chr11-18021050-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_004179.3(TPH1):c.1276C>G(p.His426Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
TPH1
NM_004179.3 missense
NM_004179.3 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 3.41
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.03544727).
BP6
?
Variant 11-18021050-G-C is Benign according to our data. Variant chr11-18021050-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 760917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPH1 | NM_004179.3 | c.1276C>G | p.His426Asp | missense_variant | 11/11 | ENST00000682019.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPH1 | ENST00000682019.1 | c.1276C>G | p.His426Asp | missense_variant | 11/11 | NM_004179.3 | P1 | ||
TPH1 | ENST00000250018.6 | c.1276C>G | p.His426Asp | missense_variant | 10/10 | 1 | P1 | ||
TPH1 | ENST00000417164.5 | c.*458C>G | 3_prime_UTR_variant, NMD_transcript_variant | 9/9 | 1 | ||||
TPH1 | ENST00000525406.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000235 AC: 59AN: 251424Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135886
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GnomAD4 exome AF: 0.000148 AC: 216AN: 1461842Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111AN XY: 727226
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GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2022 | The c.1276C>G (p.H426D) alteration is located in exon 10 (coding exon 10) of the TPH1 gene. This alteration results from a C to G substitution at nucleotide position 1276, causing the histidine (H) at amino acid position 426 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of disorder (P = 0.0397);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at