dbSNP rs8176799: TPH1:c.*1955A>G (chr11-18019036-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004179.3(TPH1):c.*1955A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,180 control chromosomes in the GnomAD database, including 2,810 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 2810 hom., cov: 33)

Exomes 𝑓: 0.10 ( 0 hom. )

Consequence

TPH1
NM_004179.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.721

Publications

2 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:

ENSG00000255448 (HGNC:):

ENSG00000255448 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

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

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH1	NM_004179.3 link	c.*1955A>G		3_prime_UTR_variant	Exon 11 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.*1955A>G		3_prime_UTR_variant	Exon 11 of 11		NM_004179.3	ENSP00000508368.1		P17752-1

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28430

AN:

152050

Hom.:

2802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.246

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.170

GnomAD4 exome

AF:

0.100

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.187

AC:

28474

AN:

152170

Hom.:

2810

Cov.:

AF XY:

0.192

AC XY:

14263

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.185

AC:

7692

AN:

41528

American (AMR)

AF:

0.243

AC:

3708

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

429

AN:

3470

East Asian (EAS)

AF:

0.246

AC:

1275

AN:

5178

South Asian (SAS)

AF:

0.317

AC:

1530

AN:

4820

European-Finnish (FIN)

AF:

0.159

AC:

1687

AN:

10592

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11574

AN:

67982

Other (OTH)

AF:

0.176

AC:

371

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1161

2323

3484

4646

5807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.181

Hom.:

656

Bravo

AF:

0.189

Asia WGS

AF:

0.267

AC:

911

AN:

3426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.72

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over