chr11-2164252-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000360.4(TH):c.1475C>T(p.Ala492Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,481,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A492A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.58

Publications

4 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.1475C>T	p.Ala492Val	missense_variant	Exon 13 of 13	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.1475C>T	p.Ala492Val	missense_variant	Exon 13 of 13	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000697

AC:

AN:

157924

AF XY:

0.0000938

show subpopulations

Gnomad AFR exome

AF:

0.000325

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000653

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

197

AN:

1329660

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

650812

show subpopulations

African (AFR)

AF:

0.000143

AC:

AN:

28058

American (AMR)

AF:

0.00

AC:

AN:

27546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19730

East Asian (EAS)

AF:

0.0000286

AC:

AN:

34972

South Asian (SAS)

AF:

0.0000150

AC:

AN:

66688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.000175

AC:

183

AN:

1044952

Other (OTH)

AF:

0.000147

AC:

AN:

54456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000499

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Uncertain:2

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 523 of the TH protein (p.Ala523Val). This variant is present in population databases (rs201219944, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 646204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 10, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1568C>T (p.A523V) alteration is located in exon 14 (coding exon 14) of the TH gene. This alteration results from a C to T substitution at nucleotide position 1568, causing the alanine (A) at amino acid position 523 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.4

M;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

N;N;.;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.027

D;D;.;D

Sift4G

Uncertain

0.028

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.76

MVP

0.98

MPC

1.3

ClinPred

0.20

GERP RS

4.3

Varity_R

0.51

gMVP

0.80

Mutation Taster

=12/88

disease causing

(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.

chr11-2164252-G-A

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