rs7305115

Variant names:

• chr12-71979082-A-G
• rs7305115
• NM_173353.4:c.936A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-71979082-A-G
• chr12-71979082-A-C
• chr12-71979082-A-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.936A>G​(p.Pro312Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,613,674 control chromosomes in the GnomAD database, including 263,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25593 hom., cov: 31)
  • Exomes 𝑓: 0.57 (237827 hom.)
• Consequence: TPH2 NM_173353.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.88
• Publications: 100 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=-0.96).
• BP6: Variant 12-71979082-A-G is Benign according to our data. Variant chr12-71979082-A-G is described in ClinVar as Benign. ClinVar VariationId is 310386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.595 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.936A>G	p.Pro312Pro	synonymous	Exon 7 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.936A>G	p.Pro312Pro	synonymous	Exon 7 of 11	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87733 AN: 151842 Hom.: 25569 Cov.: 31

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.587

GnomAD2 exomes AF: 0.562 AC: 141284 AN: 251440 AF XY: 0.562

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.642

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.569 AC: 832204 AN: 1461714 Hom.: 237827 Cov.: 56 AF XY: 0.568 AC XY: 413322 AN XY: 727184

African (AFR) AF: 0.602 AC: 20161 AN: 33468

American (AMR) AF: 0.518 AC: 23151 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16747 AN: 26136

East Asian (EAS) AF: 0.511 AC: 20279 AN: 39696

South Asian (SAS) AF: 0.529 AC: 45595 AN: 86256

European-Finnish (FIN) AF: 0.575 AC: 30689 AN: 53416

Middle Eastern (MID) AF: 0.585 AC: 3373 AN: 5768

European-Non Finnish (NFE) AF: 0.574 AC: 638017 AN: 1111866

Other (OTH) AF: 0.566 AC: 34192 AN: 60392

GnomAD4 genome AF: 0.578 AC: 87798 AN: 151960 Hom.: 25593 Cov.: 31 AF XY: 0.575 AC XY: 42720 AN XY: 74264

African (AFR) AF: 0.601 AC: 24911 AN: 41416

American (AMR) AF: 0.551 AC: 8412 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2436 AN: 5158

South Asian (SAS) AF: 0.529 AC: 2546 AN: 4816

European-Finnish (FIN) AF: 0.564 AC: 5959 AN: 10558

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39372 AN: 67958

Other (OTH) AF: 0.587 AC: 1235 AN: 2104

Alfa AF: 0.581 Hom.: 61798

Bravo AF: 0.579

Asia WGS AF: 0.499 AC: 1736 AN: 3478

EpiCase AF: 0.589

EpiControl AF: 0.585

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	-0.96
CADD	Benign	0.015
DANN	Benign	0.41
PhyloP100		-3.9
Mutation Taster		=99/1	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: rs7305115; hg19: chr12-72372862; COSMIC: COSV61591719;