rs6357

Positions:

chr11-2167008-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000360.4(TH):c.720G>A(p.Lys240=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,585,578 control chromosomes in the GnomAD database, including 69,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4911 hom., cov: 34)

Exomes 𝑓: 0.29 ( 64681 hom. )

Consequence

TH
NM_000360.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

TH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-2167008-C-T is Benign according to our data. Variant chr11-2167008-C-T is described in ClinVar as [Benign]. Clinvar id is 263258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2167008-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TH	NM_000360.4 linkuse as main transcript	c.720G>A	p.Lys240=	synonymous_variant	7/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3 linkuse as main transcript	c.813G>A	p.Lys271=	synonymous_variant	8/14		NP_954986.2
TH	NM_199293.3 linkuse as main transcript	c.801G>A	p.Lys267=	synonymous_variant	8/14		NP_954987.2
TH	XM_011520335.3 linkuse as main transcript	c.732G>A	p.Lys244=	synonymous_variant	7/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.720G>A	p.Lys240=	synonymous_variant	7/13	1	NM_000360.4	ENSP00000325951	P1	P07101-3

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

35758

AN:

152102

Hom.:

4911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.252

Gnomad EAS

AF:

0.0428

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.206

GnomAD3 exomes

AF:

0.229

AC:

46358

AN:

202788

Hom.:

6232

AF XY:

0.229

AC XY:

25132

AN XY:

109572

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.0351

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.293

Gnomad NFE exome

AF:

0.310

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.290

AC:

416356

AN:

1433358

Hom.:

64681

Cov.:

AF XY:

0.286

AC XY:

203524

AN XY:

710460

show subpopulations

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.168

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.0341

Gnomad4 SAS exome

AF:

0.146

Gnomad4 FIN exome

AF:

0.291

Gnomad4 NFE exome

AF:

0.323

Gnomad4 OTH exome

AF:

0.259

GnomAD4 genome

AF:

0.235

AC:

35751

AN:

152220

Hom.:

4911

Cov.:

AF XY:

0.230

AC XY:

17107

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.197

Gnomad4 ASJ

AF:

0.252

Gnomad4 EAS

AF:

0.0427

Gnomad4 SAS

AF:

0.143

Gnomad4 FIN

AF:

0.291

Gnomad4 NFE

AF:

0.320

Gnomad4 OTH

AF:

0.204

Alfa

AF:

0.283

Hom.:

7559

Bravo

AF:

0.222

Asia WGS

AF:

0.102

AC:

356

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 31. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over