Genetic Variant TH:p.Gly497Ser (chr11-2164238-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000360.4(TH):c.1489G>A(p.Gly497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,311,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G497D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.890

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: 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04024604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.1489G>A	p.Gly497Ser	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.1489G>A	p.Gly497Ser	missense_variant	Exon 13 of 13	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.63e-7

AC:

AN:

1311350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

640532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27398

American (AMR)

AF:

0.00

AC:

AN:

25844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19198

East Asian (EAS)

AF:

0.00

AC:

AN:

34058

South Asian (SAS)

AF:

0.00

AC:

AN:

63512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4878

European-Non Finnish (NFE)

AF:

9.66e-7

AC:

AN:

1035560

Other (OTH)

AF:

0.00

AC:

AN:

53554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Uncertain:1

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

0.041

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.22

T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

-0.73

N;.;.;.

PhyloP100

-0.89

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.76

N;N;.;N

REVEL

Uncertain

0.33

Sift

Benign

1.0

T;T;.;T

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.0030

B;B;.;B

Vest4

0.079

MutPred

0.24

Gain of glycosylation at G528 (P = 0.0366);.;.;.;

MVP

0.38

MPC

0.58

ClinPred

0.17

GERP RS

-2.5

Varity_R

0.14

gMVP

0.40

Mutation Taster

=92/8

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over