rs45538536
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_000360.4(TH):c.1368C>T(p.Ser456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,552,314 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00031 ( 2 hom. )
Consequence
TH
NM_000360.4 synonymous
NM_000360.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.90
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
Variant 11-2164359-G-A is Benign according to our data. Variant chr11-2164359-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304068.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr11-2164359-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.9 with no splicing effect.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.1368C>T | p.Ser456= | synonymous_variant | 13/13 | ENST00000352909.8 | |
TH | NM_199292.3 | c.1461C>T | p.Ser487= | synonymous_variant | 14/14 | ||
TH | NM_199293.3 | c.1449C>T | p.Ser483= | synonymous_variant | 14/14 | ||
TH | XM_011520335.3 | c.1380C>T | p.Ser460= | synonymous_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.1368C>T | p.Ser456= | synonymous_variant | 13/13 | 1 | NM_000360.4 | P1 | |
TH | ENST00000381178.5 | c.1461C>T | p.Ser487= | synonymous_variant | 14/14 | 1 | |||
TH | ENST00000381175.5 | c.1449C>T | p.Ser483= | synonymous_variant | 14/14 | 1 | |||
TH | ENST00000333684.9 | c.1086C>T | p.Ser362= | synonymous_variant | 11/11 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000237 AC: 36AN: 152202Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
36
AN:
152202
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000271 AC: 56AN: 206644Hom.: 1 AF XY: 0.000339 AC XY: 38AN XY: 112076
GnomAD3 exomes
AF:
AC:
56
AN:
206644
Hom.:
AF XY:
AC XY:
38
AN XY:
112076
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000314 AC: 440AN: 1400112Hom.: 2 Cov.: 31 AF XY: 0.000326 AC XY: 225AN XY: 691174
GnomAD4 exome
AF:
AC:
440
AN:
1400112
Hom.:
Cov.:
31
AF XY:
AC XY:
225
AN XY:
691174
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000237 AC: 36AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74338
GnomAD4 genome
?
AF:
AC:
36
AN:
152202
Hom.:
Cov.:
33
AF XY:
AC XY:
21
AN XY:
74338
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | TH: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2021 | See Variant Classification Assertion Criteria. - |
Autosomal recessive DOPA responsive dystonia Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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