chr8-132923397-C-T
Variant names:
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.Arg1530*) 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]
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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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TG | ENST00000220616.9 | c.4588C>T | p.Arg1530* | stop_gained | Exon 22 of 48 | 1 | NM_003235.5 | ENSP00000220616.4 | ||
TG | ENST00000523756.5 | n.*801C>T | non_coding_transcript_exon_variant | Exon 9 of 35 | 1 | ENSP00000428628.1 | ||||
TG | ENST00000523756.5 | n.*801C>T | 3_prime_UTR_variant | Exon 9 of 35 | 1 | ENSP00000428628.1 | ||||
TG | ENST00000519178.5 | c.145C>T | p.Arg49* | stop_gained | Exon 2 of 27 | 2 | ENSP00000430523.1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152046Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251390Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135862
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GnomAD4 exome AF: 0.000135 AC: 197AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 727234
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152046Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74260
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
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 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 18, 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. - |
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 | Jan 30, 2024 | - - |
TG-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 09, 2024 | The TG c.4588C>T variant is predicted to result in premature protein termination (p.Arg1530*). This variant, alternatively referred to as p.Arg1511X using the legacy nomenclature, has been reported in the compound heterozygous state in individuals with congenital hypothyroidism (CH) (see for example, Stoupa et al. 2021. PubMed ID: 33692749; Gutnisky et al. 2004. PubMed ID: 14764776; Targovnik et al. 1998. PubMed ID: 9588493). This variant has also been reported in the heterozygous state in an individual with mild thyroid dyshormonogenesis (Patient 31 in Oliver-Petit et al. 2021. PubMed ID: 34248839); however, the carrier members of a different family for this variant were reported as unaffected (Gutnisky et al. 2004. PubMed ID: 14764776). This variant is reported in 0.015% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
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
Vest4
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at