11-18022863-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004179.3(TPH1):c.1095T>C(p.Leu365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00668 in 1,613,620 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (35 hom.)
• Consequence: TPH1 NM_004179.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.47

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-18022863-A-G is Benign according to our data. Variant chr11-18022863-A-G is described in ClinVar as [Benign]. Clinvar id is 774690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH1	NM_004179.3	c.1095T>C	p.Leu365=	synonymous_variant	10/11	ENST00000682019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH1	ENST00000682019.1	c.1095T>C	p.Leu365=	synonymous_variant	10/11		NM_004179.3	P1
TPH1	ENST00000250018.6	c.1095T>C	p.Leu365=	synonymous_variant	9/10	1		P1
TPH1	ENST00000417164.5	c.*277T>C		3_prime_UTR_variant, NMD_transcript_variant	8/9	1
TPH1	ENST00000525406.1	n.307T>C		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 951 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00604 AC: 1516 AN: 251038 Hom.: 10 AF XY: 0.00590 AC XY: 801 AN XY: 135666

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00847

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00672 AC: 9820 AN: 1461316 Hom.: 35 Cov.: 31 AF XY: 0.00652 AC XY: 4737 AN XY: 726960

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.00758

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00624 AC: 951 AN: 152304 Hom.: 8 Cov.: 32 AF XY: 0.00616 AC XY: 459 AN XY: 74476

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00885

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00757 Hom.: 5

Bravo AF: 0.00635

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.00949

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.4
Dann	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs56151798; hg19: chr11-18044410;