11-18021050-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004179.3(TPH1):c.1276C>G(p.His426Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TPH1 NM_004179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.41

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03544727).
• BP6: Variant 11-18021050-G-C is Benign according to our data. Variant chr11-18021050-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 760917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH1	NM_004179.3	c.1276C>G	p.His426Asp	missense_variant	11/11	ENST00000682019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH1	ENST00000682019.1	c.1276C>G	p.His426Asp	missense_variant	11/11		NM_004179.3	P1
TPH1	ENST00000250018.6	c.1276C>G	p.His426Asp	missense_variant	10/10	1		P1
TPH1	ENST00000417164.5	c.*458C>G		3_prime_UTR_variant, NMD_transcript_variant	9/9	1
TPH1	ENST00000525406.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251424 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000788 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.1276C>G (p.H426D) alteration is located in exon 10 (coding exon 10) of the TPH1 gene. This alteration results from a C to G substitution at nucleotide position 1276, causing the histidine (H) at amino acid position 426 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.035	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.55
Sift	Benign	0.67	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.56
MutPred		0.42		Gain of disorder (P = 0.0397);
MVP		0.94
MPC		0.37
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.081
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs143049345; hg19: chr11-18042597;