11-2164265-T-C
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4
The NM_000360.4(TH):c.1462A>G(p.Thr488Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T488T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TH
NM_000360.4 missense
NM_000360.4 missense
Scores
1
2
16
Clinical Significance
Conservation
PhyloP100: -0.107
Publications
0 publications found
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 dystoniaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
- tyrosine hydroxylase deficiencyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
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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=0.3435854).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1340978Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 657042
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1340978
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
657042
African (AFR)
AF:
AC:
0
AN:
28456
American (AMR)
AF:
AC:
0
AN:
28416
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
20068
East Asian (EAS)
AF:
AC:
0
AN:
35394
South Asian (SAS)
AF:
AC:
0
AN:
68702
European-Finnish (FIN)
AF:
AC:
0
AN:
48632
Middle Eastern (MID)
AF:
AC:
0
AN:
5204
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1051030
Other (OTH)
AF:
AC:
0
AN:
55076
GnomAD4 genome
GnomAD4 genome
Cov.:
33
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
Mar 09, 2020
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N
REVEL
Benign
Sift
Benign
T;T;.;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;B
Vest4
MutPred
Gain of disorder (P = 0.1969);.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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