chr12-71941600-C-A

Position:

chr12-71941600-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173353.4(TPH2):c.122C>A(p.Ser41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,904 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

TPH2
NM_173353.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.94

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:

TPH2 (HGNC:):

TPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036761165).

BP6

Variant 12-71941600-C-A is Benign according to our data. Variant chr12-71941600-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 310378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00106 (161/152220) while in subpopulation EAS AF= 0.0233 (121/5184). AF 95% confidence interval is 0.02. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4 linkuse as main transcript	c.122C>A	p.Ser41Tyr	missense_variant	2/11	ENST00000333850.4	NP_775489.2	Q8IWU9-1
TPH2	XR_001748575.2 linkuse as main transcript	n.264C>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4 linkuse as main transcript	c.122C>A	p.Ser41Tyr	missense_variant	2/11	1	NM_173353.4	ENSP00000329093.3		Q8IWU9-1
TPH2	ENST00000546576.1 linkuse as main transcript	n.132C>A		non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0231

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00209

AC:

525

AN:

250984

Hom.:

AF XY:

0.00195

AC XY:

264

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0242

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00110

AC:

1614

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

800

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.0336

Gnomad4 SAS exome

AF:

0.000835

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.000960

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152220

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.0233

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.00112

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00203

AC:

246

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Major depressive disorder;C2751802:Attention deficit-hyperactivity disorder, susceptibility to, 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.056

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0037

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.12

REVEL

Uncertain

0.38

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.10

Vest4

0.36

MVP

0.27

MPC

0.44

ClinPred

0.0088

GERP RS

4.2

Varity_R

0.083

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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