chr8-132867048-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_003235.5(TG):c.48G>A(p.Trp16Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,600,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
TG
NM_003235.5 stop_gained
NM_003235.5 stop_gained
Scores
7
Clinical Significance
Conservation
PhyloP100: -0.00800
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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-132867048-G-A is Pathogenic according to our data. Variant chr8-132867048-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 915466.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TG | NM_003235.5 | c.48G>A | p.Trp16Ter | stop_gained | 1/48 | ENST00000220616.9 | NP_003226.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TG | ENST00000220616.9 | c.48G>A | p.Trp16Ter | stop_gained | 1/48 | 1 | NM_003235.5 | ENSP00000220616 | P1 | |
TG | ENST00000523901.1 | c.48G>A | p.Trp16Ter | stop_gained, NMD_transcript_variant | 1/6 | 5 | ENSP00000427871 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000437 AC: 1AN: 228978Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 123366
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GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1448632Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 719200
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Iodotyrosyl coupling defect Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University | May 14, 2020 | The patient showed classical presentation of congenital primary hypothyroidism with goitre. - |
Computational scores
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BayesDel_addAF
Benign
T
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Benign
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Pathogenic
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Benign
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Benign
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Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
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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