chr12-71949602-T-A

Variant names:

• chr12-71949602-T-A
• rs756840935
• NM_173353.4:c.555T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173353.4(TPH2):​c.555T>A​(p.Asn185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TPH2 NM_173353.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0850
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.111829996).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.555T>A	p.Asn185Lys	missense_variant	Exon 5 of 11	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.697T>A		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.555T>A	p.Asn185Lys	missense_variant	Exon 5 of 11	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.565T>A		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251176 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111218

Other (OTH) AF: 0.0000331 AC: 2 AN: 60332

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152376 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74514

African (AFR) AF: 0.00 AC: 0 AN: 41596

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.555T>A (p.N185K) alteration is located in exon 5 (coding exon 5) of the TPH2 gene. This alteration results from a T to A substitution at nucleotide position 555, causing the asparagine (N) at amino acid position 185 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.51	N
PhyloP100		0.085
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.43
Sift	Benign	0.46	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.43		Gain of methylation at N185 (P = 0.0053);
MVP		0.23
MPC		0.37
ClinPred		0.065	T
GERP RS		0.71
Varity_R		0.18
gMVP		0.41
Mutation Taster		=65/35	polymorphism

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: rs756840935; hg19: chr12-72343382;