rs6356

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.241G>A(p.Val81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,612,890 control chromosomes in the GnomAD database, including 124,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9792 hom., cov: 33)

Exomes 𝑓: 0.39 ( 115176 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.303

Publications

115 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
tyrosine hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

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 (MetaRNN=1.8311916E-6).

BP6

Variant 11-2169721-C-T is Benign according to our data. Variant chr11-2169721-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	NM_000360.4	MANE Select	c.241G>A	p.Val81Met	missense	Exon 2 of 13	NP_000351.2	P07101-3
TH	NM_199292.3		c.334G>A	p.Val112Met	missense	Exon 3 of 14	NP_954986.2	P07101-1
TH	NM_199293.3		c.322G>A	p.Val108Met	missense	Exon 3 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	ENST00000352909.8	TSL:1 MANE Select	c.241G>A	p.Val81Met	missense	Exon 2 of 13	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5	TSL:1	c.334G>A	p.Val112Met	missense	Exon 3 of 14	ENSP00000370571.1	P07101-1
TH	ENST00000381175.5	TSL:1	c.322G>A	p.Val108Met	missense	Exon 3 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50411

AN:

151958

Hom.:

9794

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.243

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.554

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.366

GnomAD2 exomes

AF:

0.429

AC:

106793

AN:

249138

AF XY:

0.438

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.435

Gnomad ASJ exome

AF:

0.387

Gnomad EAS exome

AF:

0.799

Gnomad FIN exome

AF:

0.454

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.423

GnomAD4 exome

AF:

0.387

AC:

564672

AN:

1460814

Hom.:

115176

Cov.:

AF XY:

0.392

AC XY:

285107

AN XY:

726702

show subpopulations

African (AFR)

AF:

0.134

AC:

4480

AN:

33478

American (AMR)

AF:

0.427

AC:

19082

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

10212

AN:

26128

East Asian (EAS)

AF:

0.742

AC:

29459

AN:

39696

South Asian (SAS)

AF:

0.551

AC:

47544

AN:

86244

European-Finnish (FIN)

AF:

0.446

AC:

23449

AN:

52570

Middle Eastern (MID)

AF:

0.472

AC:

2716

AN:

5752

European-Non Finnish (NFE)

AF:

0.363

AC:

403276

AN:

1111858

Other (OTH)

AF:

0.405

AC:

24454

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

21128

42257

63385

84514

105642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12938

25876

38814

51752

64690

<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:

0.331

AC:

50412

AN:

152076

Hom.:

9792

Cov.:

AF XY:

0.343

AC XY:

25518

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.144

AC:

5965

AN:

41512

American (AMR)

AF:

0.376

AC:

5753

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

1337

AN:

3468

East Asian (EAS)

AF:

0.790

AC:

4061

AN:

5142

South Asian (SAS)

AF:

0.553

AC:

2667

AN:

4824

European-Finnish (FIN)

AF:

0.447

AC:

4741

AN:

10610

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.364

AC:

24735

AN:

67912

Other (OTH)

AF:

0.369

AC:

777

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1621

3242

4864

6485

8106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.362

Hom.:

17022

Bravo

AF:

0.321

TwinsUK

AF:

0.372

AC:

1380

ALSPAC

AF:

0.347

AC:

1337

ESP6500AA

AF:

0.142

AC:

623

ESP6500EA

AF:

0.363

AC:

3121

ExAC

AF:

0.422

AC:

51182

Asia WGS

AF:

0.638

AC:

2220

AN:

3478

EpiCase

AF:

0.376

EpiControl

AF:

0.378

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive DOPA responsive dystonia (7)

not specified (4)

not provided (3)

Schizophrenia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.27

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0000018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

PhyloP100

-0.30

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.15

REVEL

Benign

0.18

Sift

Benign

0.22

Sift4G

Benign

0.19

Polyphen

0.016

Vest4

0.038

MPC

0.046

ClinPred

0.00092

GERP RS

-1.8

Varity_R

0.034

gMVP

0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over