chr11-2164267-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000360.4(TH):c.1460A>G(p.Asp487Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,498,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D487H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.66

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22986656).

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.1460A>G	p.Asp487Gly	missense	Exon 13 of 13	NP_000351.2	P07101-3
TH	NM_199292.3		c.1553A>G	p.Asp518Gly	missense	Exon 14 of 14	NP_954986.2	P07101-1
TH	NM_199293.3		c.1541A>G	p.Asp514Gly	missense	Exon 14 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.1460A>G	p.Asp487Gly	missense	Exon 13 of 13	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5	TSL:1	c.1553A>G	p.Asp518Gly	missense	Exon 14 of 14	ENSP00000370571.1	P07101-1
TH	ENST00000381175.5	TSL:1	c.1541A>G	p.Asp514Gly	missense	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000301

AC:

AN:

166056

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000510

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000499

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1346014

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

659580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28676

American (AMR)

AF:

0.0000346

AC:

AN:

28908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20226

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35772

South Asian (SAS)

AF:

0.00

AC:

AN:

69518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5232

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

1053582

Other (OTH)

AF:

0.0000723

AC:

AN:

55316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000394

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000995

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive DOPA responsive dystonia (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.28

PhyloP100

3.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.59

REVEL

Uncertain

0.42

Sift

Benign

0.48

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.097

MVP

0.96

MPC

0.77

ClinPred

0.053

GERP RS

3.8

Varity_R

0.32

gMVP

0.51

Mutation Taster

=64/36

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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