NM_000360.4:c.23C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000360.4(TH):​c.23C>T​(p.Thr8Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,612,472 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3908478).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
THNM_000360.4 linkc.23C>T p.Thr8Met 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
THENST00000352909.8 linkc.23C>T p.Thr8Met missense_variant Exon 1 of 13 1 NM_000360.4 ENSP00000325951.4 P07101-3

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000808
AC:
20
AN:
247550
AF XY:
0.0000894
show subpopulations
Gnomad AFR exome
AF:
0.000309
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000991
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000698
AC:
102
AN:
1460304
Hom.:
0
Cov.:
31
AF XY:
0.0000840
AC XY:
61
AN XY:
726530
show subpopulations
African (AFR)
AF:
0.000209
AC:
7
AN:
33472
American (AMR)
AF:
0.0000447
AC:
2
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.0000928
AC:
8
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52334
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5620
European-Non Finnish (NFE)
AF:
0.0000702
AC:
78
AN:
1111804
Other (OTH)
AF:
0.000116
AC:
7
AN:
60352
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.459
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000657
AC:
10
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74336
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41434
American (AMR)
AF:
0.000327
AC:
5
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.000478
AC:
1
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000282
Hom.:
0
Bravo
AF:
0.0000907
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:2
Nov 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 8 of the TH protein (p.Thr8Met). This variant is present in population databases (rs373964946, 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: 576292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TH protein function. 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. -

Nov 11, 2019
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Inborn genetic diseases Uncertain:1
Jun 11, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.23C>T (p.T8M) alteration is located in exon 1 (coding exon 1) of the TH gene. This alteration results from a C to T substitution at nucleotide position 23, causing the threonine (T) at amino acid position 8 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TH: PM2 -

Intellectual disability Uncertain:1
Mar 27, 2020
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
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
0.10
BayesDel_addAF
Benign
-0.096
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;.;.;.
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.62
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Benign
0.39
T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.81
L;L;L;L
PhyloP100
5.2
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.77
N;N;N;N
REVEL
Uncertain
0.33
Sift
Uncertain
0.0040
D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D
Polyphen
0.98
D;D;.;P
Vest4
0.38
MVP
0.95
MPC
0.26
ClinPred
0.20
T
GERP RS
2.9
PromoterAI
0.042
Neutral
Varity_R
0.10
gMVP
0.36
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs373964946; hg19: chr11-2192994; API