rs4290270

Variant names:

• chr12-72022455-A-T
• rs4290270
• NM_173353.4:c.1125A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173353.4(TPH2):​c.1125A>T​(p.Ala375Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,612,974 control chromosomes in the GnomAD database, including 305,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23593 hom., cov: 32)
  • Exomes 𝑓: 0.62 (282193 hom.)
• Consequence: TPH2 NM_173353.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.959
• Publications: 82 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-72022455-A-T is Benign according to our data. Variant chr12-72022455-A-T is described in ClinVar as Benign. ClinVar VariationId is 310388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.959 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 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.1125A>T	p.Ala375Ala	synonymous	Exon 9 of 11	NP_775489.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.1125A>T	p.Ala375Ala	synonymous	Exon 9 of 11	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83252 AN: 151848 Hom.: 23583 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.575

GnomAD2 exomes AF: 0.571 AC: 143420 AN: 251170 AF XY: 0.575

Gnomad AFR exome AF: 0.405

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.480

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.618 AC: 903562 AN: 1461008 Hom.: 282193 Cov.: 45 AF XY: 0.617 AC XY: 448266 AN XY: 726874

African (AFR) AF: 0.405 AC: 13556 AN: 33458

American (AMR) AF: 0.521 AC: 23315 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 16180 AN: 26130

East Asian (EAS) AF: 0.528 AC: 20971 AN: 39692

South Asian (SAS) AF: 0.520 AC: 44857 AN: 86240

European-Finnish (FIN) AF: 0.536 AC: 28603 AN: 53400

Middle Eastern (MID) AF: 0.594 AC: 3424 AN: 5762

European-Non Finnish (NFE) AF: 0.645 AC: 716657 AN: 1111238

Other (OTH) AF: 0.596 AC: 35999 AN: 60376

GnomAD4 genome AF: 0.548 AC: 83295 AN: 151966 Hom.: 23593 Cov.: 32 AF XY: 0.542 AC XY: 40290 AN XY: 74278

African (AFR) AF: 0.410 AC: 16985 AN: 41418

American (AMR) AF: 0.554 AC: 8449 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2113 AN: 3472

East Asian (EAS) AF: 0.480 AC: 2475 AN: 5160

South Asian (SAS) AF: 0.519 AC: 2499 AN: 4812

European-Finnish (FIN) AF: 0.509 AC: 5383 AN: 10572

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.639 AC: 43395 AN: 67960

Other (OTH) AF: 0.572 AC: 1209 AN: 2114

Alfa AF: 0.616 Hom.: 9470

Bravo AF: 0.546

Asia WGS AF: 0.480 AC: 1667 AN: 3478

EpiCase AF: 0.640

EpiControl AF: 0.637

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Tryptophan 5-monooxygenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-0.96
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: rs4290270; hg19: chr12-72416235; COSMIC: COSV61590307;