12-71960697-A-G

Variant names:

• chr12-71960697-A-G
• rs6582072
• NM_173353.4:c.608+11042A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.608+11042A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 152,172 control chromosomes in the GnomAD database, including 48,050 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 0.79 (48050 hom., cov: 33)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 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.608+11042A>G		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.608+11042A>G		intron	N/A	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.619-856A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120488 AN: 152054 Hom.: 48014 Cov.: 33

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.804

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.792 AC: 120572 AN: 152172 Hom.: 48050 Cov.: 33 AF XY: 0.793 AC XY: 59009 AN XY: 74382

African (AFR) AF: 0.701 AC: 29085 AN: 41484

American (AMR) AF: 0.837 AC: 12803 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 2942 AN: 3472

East Asian (EAS) AF: 0.841 AC: 4351 AN: 5174

South Asian (SAS) AF: 0.782 AC: 3768 AN: 4818

European-Finnish (FIN) AF: 0.811 AC: 8590 AN: 10594

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56284 AN: 68012

Other (OTH) AF: 0.801 AC: 1693 AN: 2114

Alfa AF: 0.808 Hom.: 7224

Bravo AF: 0.791

Asia WGS AF: 0.751 AC: 2614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.1
DANN	Benign	0.67
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs6582072;

hg19: chr12-72354477;