8-132923397-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003235.5(TG):c.4588C>T(p.Arg1530Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,922 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
TG
NM_003235.5 stop_gained
NM_003235.5 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 1.83
Genes affected
TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-132923397-C-T is Pathogenic according to our data. Variant chr8-132923397-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TG | NM_003235.5 | c.4588C>T | p.Arg1530Ter | stop_gained | 22/48 | ENST00000220616.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TG | ENST00000220616.9 | c.4588C>T | p.Arg1530Ter | stop_gained | 22/48 | 1 | NM_003235.5 | P1 | |
TG | ENST00000523756.5 | c.*801C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/35 | 1 | ||||
TG | ENST00000519178.5 | c.148C>T | p.Arg50Ter | stop_gained | 2/27 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152046Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
17
AN:
152046
Hom.:
Cov.:
31
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: 0.0000835 AC: 21AN: 251390Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135862
GnomAD3 exomes
AF:
AC:
21
AN:
251390
Hom.:
AF XY:
AC XY:
16
AN XY:
135862
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: 0.000135 AC: 197AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 727234
GnomAD4 exome
AF:
AC:
197
AN:
1461876
Hom.:
Cov.:
31
AF XY:
AC XY:
108
AN XY:
727234
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: 0.000112 AC: 17AN: 152046Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74260
GnomAD4 genome
?
AF:
AC:
17
AN:
152046
Hom.:
Cov.:
31
AF XY:
AC XY:
5
AN XY:
74260
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:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
8
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Iodotyrosyl coupling defect Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 07, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.Arg1530*) in the TG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TG are known to be pathogenic (PMID: 19837936, 23164529). This variant is present in population databases (rs121912646, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of thyroid dyshormonogenesis (PMID: 8325944, 11484898, 14764776, 28444304, 33692749, 34248839). This variant is also known as p.Arg1510* and p.Arg1511*. ClinVar contains an entry for this variant (Variation ID: 12691). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2023 | Published functional studies demonstrate a damaging effect (Targovnik et al., 1993); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9588493, 8325944, 34200080, 25525159, 11484898, 14764776, 28444304, 34426522, 34248839, 33692749, 35177841) - |
Congenital hypothyroidism Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Polak associated Lab, IMAGINE Institute | - | - - |
Iodotyrosyl coupling defect;C1842444:Autoimmune thyroid disease, susceptibility to, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
ClinPred
T
GERP RS
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