11-18025708-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004179.3(TPH1):c.804-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,613,054 control chromosomes in the GnomAD database, including 123,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (9477 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114044 hom.)
• Consequence: TPH1 NM_004179.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0007345
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.630

Genes affected

TPH1 (HGNC:12008): (tryptophan hydroxylase 1) This gene encodes a member of the aromatic amino 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 have been associated with an elevated risk for a variety of diseases and disorders, including schizophrenia, somatic anxiety, anger-related traits, bipolar disorder, suicidal behavior, addictions, and others.[provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-18025708-G-T is Benign according to our data. Variant chr11-18025708-G-T is described in ClinVar as [Benign]. Clinvar id is 3060644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH1	NM_004179.3	c.804-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000682019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH1	ENST00000682019.1	c.804-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004179.3	P1
TPH1	ENST00000250018.6	c.804-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
TPH1	ENST00000417164.5	c.607-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51501 AN: 151950 Hom.: 9480 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.390 AC: 98099 AN: 251264 Hom.: 19785 AF XY: 0.391 AC XY: 53142 AN XY: 135802

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.464

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.391 AC: 571955 AN: 1460986 Hom.: 114044 Cov.: 41 AF XY: 0.391 AC XY: 284282 AN XY: 726840

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.522

Gnomad4 EAS exome AF: 0.484

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.339 AC: 51503 AN: 152068 Hom.: 9477 Cov.: 32 AF XY: 0.343 AC XY: 25456 AN XY: 74316

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.523

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.353

Alfa AF: 0.369 Hom.: 6911

Bravo AF: 0.330

EpiCase AF: 0.389

EpiControl AF: 0.402

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TPH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	6.4
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00073
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1799913; hg19: chr11-18047255; COSMIC: COSV51457405; COSMIC: COSV51457405;