11-18042430-A-T

Position:

• chr11-18042430-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004179.3(TPH1):​c.-26-1642T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 434,080 control chromosomes in the GnomAD database, including 91,278 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 0.65 (32370 hom., cov: 31)
  • Exomes 𝑓: 0.64 (58908 hom.)
• Consequence: TPH1 NM_004179.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH1	NM_004179.3	c.-26-1642T>A		intron_variant		ENST00000682019.1	NP_004170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH1	ENST00000682019.1	c.-26-1642T>A		intron_variant			NM_004179.3	ENSP00000508368	P1
TPH1	ENST00000528338.1			upstream_gene_variant		3		ENSP00000436081

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98874 AN: 151900 Hom.: 32331 Cov.: 31

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.648

GnomAD4 exome AF: 0.643 AC: 181435 AN: 282062 Hom.: 58908 Cov.: 0 AF XY: 0.633 AC XY: 102070 AN XY: 161188

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.732

Gnomad4 NFE exome AF: 0.665

Gnomad4 OTH exome AF: 0.662

GnomAD4 genome AF: 0.651 AC: 98970 AN: 152018 Hom.: 32370 Cov.: 31 AF XY: 0.652 AC XY: 48460 AN XY: 74288

Gnomad4 AFR AF: 0.649

Gnomad4 AMR AF: 0.595

Gnomad4 ASJ AF: 0.732

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.737

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.643

Alfa AF: 0.657 Hom.: 4098

Bravo AF: 0.646

Asia WGS AF: 0.585 AC: 2036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs623580; hg19: chr11-18063977;