rs4290270

chr12-72022455-A-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_173353.4(TPH2):c.1125A>T(p.Ala375=) 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, single submitter B:1
• Conservation: PhyloP100: -0.959

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]

ACMG classification

Verdict is Benign. Variant got -15 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 id is 310388.Status of the report is criteria_provided_single_submitter, 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.1125A>T	p.Ala375=	synonymous_variant	9/11	ENST00000333850.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.1125A>T	p.Ala375=	synonymous_variant	9/11	1	NM_173353.4	P1

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

GnomAD3 exomes AF: 0.571 AC: 143420 AN: 251170 Hom.: 41870 AF XY: 0.575 AC XY: 78021 AN XY: 135718

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 SAS exome AF: 0.523

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

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.645

Gnomad4 OTH exome AF: 0.596

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

Gnomad4 AFR AF: 0.410

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.639

Gnomad4 OTH AF: 0.572

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.3
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs4290270; hg19: chr12-72416235; COSMIC: COSV61590307;