Genetic Variant TH:p.Thr8Lys (chr11-2171764-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000360.4(TH):c.23C>A(p.Thr8Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.21

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35497385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 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.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 13	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460304

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111806

Other (OTH)

AF:

0.00

AC:

AN:

60352

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

0.81

L;L;L;L

PhyloP100

5.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.95

N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.030

D;T;T;T

Polyphen

0.41

B;B;.;B

Vest4

0.32

MutPred

0.19

Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);

MVP

0.93

MPC

0.057

ClinPred

0.40

GERP RS

2.9

PromoterAI

0.0053

Neutral

(source)

Varity_R

0.19

gMVP

0.42

Mutation Taster

=87/13

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

Computational scores

Splicing

Publications

Other links and lift over