11-18029259-T-G

Position:

• chr11-18029259-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004179.3(TPH1):​c.573A>C​(p.Arg191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPH1 NM_004179.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH1	NM_004179.3	c.573A>C	p.Arg191Ser	missense_variant	6/11	ENST00000682019.1	NP_004170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH1	ENST00000682019.1	c.573A>C	p.Arg191Ser	missense_variant	6/11		NM_004179.3	ENSP00000508368	P1
TPH1	ENST00000250018.6	c.573A>C	p.Arg191Ser	missense_variant	5/10	1		ENSP00000250018	P1
TPH1	ENST00000417164.5	c.470+253A>C		intron_variant, NMD_transcript_variant		1		ENSP00000403831

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.573A>C (p.R191S) alteration is located in exon 5 (coding exon 5) of the TPH1 gene. This alteration results from a A to C substitution at nucleotide position 573, causing the arginine (R) at amino acid position 191 to be replaced by a serine (S). 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	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0020
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.72
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.13	B
Vest4		0.83
MutPred		0.46		Gain of ubiquitination at K195 (P = 0.1974);
MVP		0.90
MPC		0.53
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.76
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-18050806;