chr11-2167882-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000360.4(TH):​c.628G>T​(p.Ala210Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A210T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.76

Publications

3 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: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr11-2167882-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
THNM_000360.4 linkc.628G>T p.Ala210Ser missense_variant Exon 5 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.628G>T p.Ala210Ser missense_variant Exon 5 of 13 1 NM_000360.4 ENSP00000325951.4 P07101-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
240286
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455900
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
723748
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33374
American (AMR)
AF:
0.00
AC:
0
AN:
44354
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26020
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39446
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85282
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51762
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5758
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109738
Other (OTH)
AF:
0.00
AC:
0
AN:
60166
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000244
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 23, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.721G>T (p.A241S) alteration is located in exon 6 (coding exon 6) of the TH gene. This alteration results from a G to T substitution at nucleotide position 721, causing the alanine (A) at amino acid position 241 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive DOPA responsive dystonia Uncertain:1
Mar 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with TH-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 241 of the TH protein (p.Ala241Ser). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;.;.;.
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Uncertain
2.7
M;.;.;.
PhyloP100
3.8
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-2.8
D;D;.;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.010
D;D;.;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.72
MutPred
0.86
Gain of MoRF binding (P = 0.1009);.;.;.;
MVP
0.95
MPC
0.31
ClinPred
0.95
D
GERP RS
3.1
PromoterAI
-0.0087
Neutral
Varity_R
0.72
gMVP
0.78
Mutation Taster
=27/73
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: rs1260455415; hg19: chr11-2189112; API