12-71956246-T-A

Variant names:

• chr12-71956246-T-A
• rs7955501
• NM_173353.4:c.608+6591T>A

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+6591T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,026 control chromosomes in the GnomAD database, including 26,144 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 0.58 (26144 hom., cov: 31)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.64 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+6591T>A		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+6591T>A		intron	N/A	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.619-5307T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88601 AN: 151908 Hom.: 26112 Cov.: 31

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.583 AC: 88682 AN: 152026 Hom.: 26144 Cov.: 31 AF XY: 0.586 AC XY: 43527 AN XY: 74302

African (AFR) AF: 0.511 AC: 21204 AN: 41462

American (AMR) AF: 0.635 AC: 9693 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2239 AN: 3468

East Asian (EAS) AF: 0.610 AC: 3141 AN: 5146

South Asian (SAS) AF: 0.659 AC: 3173 AN: 4814

European-Finnish (FIN) AF: 0.581 AC: 6144 AN: 10580

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 41016 AN: 67966

Other (OTH) AF: 0.613 AC: 1294 AN: 2112

Alfa AF: 0.584 Hom.: 3083

Bravo AF: 0.582

Asia WGS AF: 0.676 AC: 2348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.78
PhyloP100		0.12
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

Other links and lift over

dbSNP: rs7955501; hg19: chr12-72350026;