chr11-2166625-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000360.4(TH):c.977+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,578,486 control chromosomes in the GnomAD database, including 91,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6578 hom., cov: 35)

Exomes 𝑓: 0.34 ( 85125 hom. )

Consequence

TH
NM_000360.4 splice_region, intron

Scores

Splicing: ADA: 0.0001468

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0860

Publications

14 publications found

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 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

TH links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 11-2166625-G-C is Benign according to our data. Variant chr11-2166625-G-C is described in ClinVar as Benign. ClinVar VariationId is 263250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.977+8C>G		splice_region_variant, intron_variant	Intron 8 of 12	ENST00000352909.8	NP_000351.2	P07101-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 link	c.977+8C>G		splice_region_variant, intron_variant	Intron 8 of 12	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41314

AN:

152114

Hom.:

6578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.457

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.0433

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.279

AC:

50436

AN:

180986

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.367

Gnomad EAS exome

AF:

0.0376

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.371

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.335

AC:

478037

AN:

1426256

Hom.:

85125

Cov.:

AF XY:

0.331

AC XY:

233704

AN XY:

706218

show subpopulations

African (AFR)

AF:

0.127

AC:

4178

AN:

33008

American (AMR)

AF:

0.236

AC:

9151

AN:

38768

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

9224

AN:

25428

East Asian (EAS)

AF:

0.0361

AC:

1378

AN:

38188

South Asian (SAS)

AF:

0.171

AC:

13935

AN:

81616

European-Finnish (FIN)

AF:

0.331

AC:

16240

AN:

49132

Middle Eastern (MID)

AF:

0.225

AC:

1280

AN:

5690

European-Non Finnish (NFE)

AF:

0.369

AC:

404464

AN:

1095326

Other (OTH)

AF:

0.308

AC:

18187

AN:

59100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

21850

43700

65551

87401

109251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12540

25080

37620

50160

62700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.271

AC:

41307

AN:

152230

Hom.:

6578

Cov.:

AF XY:

0.265

AC XY:

19748

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.136

AC:

5667

AN:

41572

American (AMR)

AF:

0.253

AC:

3867

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

1258

AN:

3470

East Asian (EAS)

AF:

0.0432

AC:

224

AN:

5180

South Asian (SAS)

AF:

0.160

AC:

772

AN:

4832

European-Finnish (FIN)

AF:

0.334

AC:

3543

AN:

10608

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.367

AC:

24943

AN:

67962

Other (OTH)

AF:

0.260

AC:

549

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1574

3149

4723

6298

7872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.306

Hom.:

2477

Bravo

AF:

0.260

Asia WGS

AF:

0.115

AC:

401

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Benign:6

Feb 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

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

- -

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

- -

Jan 12, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

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 42% 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: 39. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.3

(source)

DANN

Benign

0.89

PhyloP100

-0.086

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over