11-18042430-A-T

Variant names:

• chr11-18042430-A-T
• rs623580
• NM_004179.3:c.-26-1642T>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 publications found

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]

ENSG00000302464 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TPH1	NM_004179.3	c.-26-1642T>A		intron_variant	Intron 1 of 10	ENST00000682019.1	NP_004170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH1	ENST00000682019.1	c.-26-1642T>A		intron_variant	Intron 1 of 10		NM_004179.3	ENSP00000508368.1

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

African (AFR) AF: 0.655 AC: 4876 AN: 7440

American (AMR) AF: 0.610 AC: 13459 AN: 22080

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 7324 AN: 9950

East Asian (EAS) AF: 0.670 AC: 5834 AN: 8702

South Asian (SAS) AF: 0.549 AC: 29954 AN: 54534

European-Finnish (FIN) AF: 0.732 AC: 8859 AN: 12096

Middle Eastern (MID) AF: 0.614 AC: 1629 AN: 2652

European-Non Finnish (NFE) AF: 0.665 AC: 100653 AN: 151254

Other (OTH) AF: 0.662 AC: 8847 AN: 13354

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

African (AFR) AF: 0.649 AC: 26907 AN: 41436

American (AMR) AF: 0.595 AC: 9080 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2542 AN: 3472

East Asian (EAS) AF: 0.656 AC: 3396 AN: 5180

South Asian (SAS) AF: 0.520 AC: 2509 AN: 4828

European-Finnish (FIN) AF: 0.737 AC: 7778 AN: 10552

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44585 AN: 67978

Other (OTH) AF: 0.643 AC: 1357 AN: 2110

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
PhyloP100		-0.37
PromoterAI		-0.0034	Neutral

Splicing

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

Other links and lift over

dbSNP: rs623580; hg19: chr11-18063977;