12-71942014-A-G

Variant names:

• chr12-71942014-A-G
• rs7954758
• NM_173353.4:c.255+281A>G

Variant summary

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

The NM_173353.4(TPH2):​c.255+281A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0975 in 152,250 control chromosomes in the GnomAD database, including 843 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 0.097 (843 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• Publications: 8 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.255+281A>G		intron_variant	Intron 2 of 10	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.397+281A>G		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.255+281A>G		intron_variant	Intron 2 of 10	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.265+281A>G		intron_variant	Intron 2 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0973 AC: 14802 AN: 152132 Hom.: 837 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0874

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0975 AC: 14839 AN: 152250 Hom.: 843 Cov.: 32 AF XY: 0.0993 AC XY: 7395 AN XY: 74448

African (AFR) AF: 0.137 AC: 5673 AN: 41544

American (AMR) AF: 0.0880 AC: 1346 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3464

East Asian (EAS) AF: 0.170 AC: 880 AN: 5182

South Asian (SAS) AF: 0.177 AC: 856 AN: 4824

European-Finnish (FIN) AF: 0.0756 AC: 802 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0720 AC: 4898 AN: 68012

Other (OTH) AF: 0.0917 AC: 194 AN: 2116

Alfa AF: 0.0912 Hom.: 112

Bravo AF: 0.0978

Asia WGS AF: 0.213 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.63
PhyloP100		-0.036
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: rs7954758; hg19: chr12-72335794;