11-2167008-C-T

Variant names:

• chr11-2167008-C-T
• rs6357
• NM_000360.4:c.720G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.720G>A​(p.Lys240Lys) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.75
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 263258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.720G>A	p.Lys240Lys	synonymous	Exon 7 of 13	NP_000351.2
	TH	NM_199292.3		c.813G>A	p.Lys271Lys	synonymous	Exon 8 of 14	NP_954986.2
	TH	NM_199293.3		c.801G>A	p.Lys267Lys	synonymous	Exon 8 of 14	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.720G>A	p.Lys240Lys	synonymous	Exon 7 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.813G>A	p.Lys271Lys	synonymous	Exon 8 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.801G>A	p.Lys267Lys	synonymous	Exon 8 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35758 AN: 152102 Hom.: 4911 Cov.: 34

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

GnomAD2 exomes AF: 0.229 AC: 46358 AN: 202788 AF XY: 0.229

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 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.: 60 AF XY: 0.286 AC XY: 203524 AN XY: 710460

African (AFR) AF: 0.118 AC: 3899 AN: 32934

American (AMR) AF: 0.168 AC: 6907 AN: 41158

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6433 AN: 25540

East Asian (EAS) AF: 0.0341 AC: 1305 AN: 38298

South Asian (SAS) AF: 0.146 AC: 12013 AN: 82238

European-Finnish (FIN) AF: 0.291 AC: 14573 AN: 50054

Middle Eastern (MID) AF: 0.128 AC: 731 AN: 5722

European-Non Finnish (NFE) AF: 0.323 AC: 355109 AN: 1098104

Other (OTH) AF: 0.259 AC: 15386 AN: 59310

GnomAD4 genome AF: 0.235 AC: 35751 AN: 152220 Hom.: 4911 Cov.: 34 AF XY: 0.230 AC XY: 17107 AN XY: 74426

African (AFR) AF: 0.127 AC: 5280 AN: 41560

American (AMR) AF: 0.197 AC: 3018 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 876 AN: 3472

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5176

South Asian (SAS) AF: 0.143 AC: 689 AN: 4832

European-Finnish (FIN) AF: 0.291 AC: 3080 AN: 10602

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21732 AN: 67962

Other (OTH) AF: 0.204 AC: 430 AN: 2112

Alfa AF: 0.277 Hom.: 10740

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

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:6

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6357; hg19: chr11-2188238; COSMIC: COSV60767253; COSMIC: COSV60767253;