12-71994594-G-T

Variant names:

• chr12-71994594-G-T
• rs1007023
• NM_173353.4:c.1068+29G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.1068+29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 1,612,220 control chromosomes in the GnomAD database, including 588,440 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 0.85 (54709 hom., cov: 32)
  • Exomes 𝑓: 0.85 (533731 hom.)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.145
• Publications: 18 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	NM_173353.4	MANE Select	c.1068+29G>T		intron	N/A	NP_775489.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.1068+29G>T		intron	N/A	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128800 AN: 152046 Hom.: 54658 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.855

GnomAD2 exomes AF: 0.873 AC: 219012 AN: 250926 AF XY: 0.873

Gnomad AFR exome AF: 0.820

Gnomad AMR exome AF: 0.925

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.955

Gnomad FIN exome AF: 0.836

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.854 AC: 1247414 AN: 1460056 Hom.: 533731 Cov.: 36 AF XY: 0.855 AC XY: 621378 AN XY: 726374

African (AFR) AF: 0.817 AC: 27305 AN: 33438

American (AMR) AF: 0.918 AC: 41040 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 23056 AN: 26090

East Asian (EAS) AF: 0.966 AC: 38304 AN: 39632

South Asian (SAS) AF: 0.908 AC: 78253 AN: 86188

European-Finnish (FIN) AF: 0.837 AC: 44576 AN: 53242

Middle Eastern (MID) AF: 0.845 AC: 4866 AN: 5758

European-Non Finnish (NFE) AF: 0.845 AC: 938442 AN: 1110688

Other (OTH) AF: 0.855 AC: 51572 AN: 60316

GnomAD4 genome AF: 0.847 AC: 128910 AN: 152164 Hom.: 54709 Cov.: 32 AF XY: 0.849 AC XY: 63181 AN XY: 74388

African (AFR) AF: 0.813 AC: 33743 AN: 41498

American (AMR) AF: 0.884 AC: 13518 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3022 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4956 AN: 5172

South Asian (SAS) AF: 0.914 AC: 4407 AN: 4824

European-Finnish (FIN) AF: 0.825 AC: 8726 AN: 10580

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.848 AC: 57650 AN: 68004

Other (OTH) AF: 0.856 AC: 1804 AN: 2108

Alfa AF: 0.852 Hom.: 28374

Bravo AF: 0.849

Asia WGS AF: 0.922 AC: 3205 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs1007023; hg19: chr12-72388374; COSMIC: COSV61594791;