11-2164325-C-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000360.4(TH):c.1402G>T(p.Val468Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V468M) has been classified as Likely pathogenic.
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
4
6
9
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 4.22
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: Likely_pathogenic. The variant received 6 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000360.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2164325-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412030.
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: 1387596Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 683176
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1387596
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
683176
African (AFR)
AF:
AC:
0
AN:
30388
American (AMR)
AF:
AC:
0
AN:
36132
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
22634
East Asian (EAS)
AF:
AC:
0
AN:
36640
South Asian (SAS)
AF:
AC:
0
AN:
77130
European-Finnish (FIN)
AF:
AC:
0
AN:
50404
Middle Eastern (MID)
AF:
AC:
0
AN:
5460
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1071646
Other (OTH)
AF:
AC:
0
AN:
57162
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N
REVEL
Uncertain
Sift
Benign
T;T;.;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;B
Vest4
MutPred
Loss of sheet (P = 0.1398);.;.;.;
MVP
MPC
ClinPred
D
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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