rs41265611

Variant names:

• chr12-71939143-ATCT-A
• rs41265611
• NM_173353.4:c.105+56_105+58delTCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_173353.4(TPH2):​c.105+56_105+58delTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,354,670 control chromosomes in the GnomAD database, including 5,886 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1287 hom., cov: 30)
  • Exomes 𝑓: 0.079 (4599 hom.)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• attention deficit-hyperactivity disorder, susceptibility to, 7

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173353.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	NM_173353.4	MANE Select	c.105+56_105+58delTCT		intron	N/A	NP_775489.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.105+53_105+55delTCT		intron	N/A	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.115+53_115+55delTCT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17672 AN: 151982 Hom.: 1279 Cov.: 30

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0968

GnomAD2 exomes AF: 0.100 AC: 22249 AN: 221716 AF XY: 0.0964

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.0674

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0789

GnomAD4 exome AF: 0.0785 AC: 94408 AN: 1202570 Hom.: 4599 AF XY: 0.0796 AC XY: 48609 AN XY: 610308

African (AFR) AF: 0.210 AC: 5919 AN: 28182

American (AMR) AF: 0.125 AC: 5263 AN: 42100

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 889 AN: 24482

East Asian (EAS) AF: 0.135 AC: 5133 AN: 37916

South Asian (SAS) AF: 0.120 AC: 9596 AN: 79810

European-Finnish (FIN) AF: 0.0713 AC: 3281 AN: 46030

Middle Eastern (MID) AF: 0.0687 AC: 364 AN: 5298

European-Non Finnish (NFE) AF: 0.0672 AC: 59572 AN: 886890

Other (OTH) AF: 0.0847 AC: 4391 AN: 51862

GnomAD4 genome AF: 0.117 AC: 17720 AN: 152100 Hom.: 1287 Cov.: 30 AF XY: 0.117 AC XY: 8678 AN XY: 74364

African (AFR) AF: 0.211 AC: 8751 AN: 41462

American (AMR) AF: 0.0957 AC: 1462 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3470

East Asian (EAS) AF: 0.167 AC: 861 AN: 5168

South Asian (SAS) AF: 0.113 AC: 544 AN: 4824

European-Finnish (FIN) AF: 0.0758 AC: 803 AN: 10592

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0720 AC: 4894 AN: 67994

Other (OTH) AF: 0.100 AC: 211 AN: 2108

Alfa AF: 0.0885 Hom.: 135

Bravo AF: 0.122

Asia WGS AF: 0.165 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41265611;

hg19: chr12-72332923;

COSMIC: COSV61591891;