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rs199599591

chr8-132941493-C-Achr8-132941493-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.5184C>A(p.Cys1728Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,052 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C1728C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TG
NM_003235.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -0.0460
Variant links:
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
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-132941493-C-A is Pathogenic according to our data. Variant chr8-132941493-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 208619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGNM_003235.5 linkuse as main transcriptc.5184C>A p.Cys1728Ter stop_gained 26/48 ENST00000220616.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGENST00000220616.9 linkuse as main transcriptc.5184C>A p.Cys1728Ter stop_gained 26/481 NM_003235.5 P1P01266-1
TGENST00000523756.5 linkuse as main transcriptc.*1397C>A 3_prime_UTR_variant, NMD_transcript_variant 13/351
TGENST00000519178.5 linkuse as main transcriptc.599+5629C>A intron_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000854
AC:
13
AN:
152162
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251462
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00188
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000540
AC:
79
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00203
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000854
AC:
13
AN:
152162
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000113
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000741
AC:
9
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Iodotyrosyl coupling defect Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 08, 2014The Cys1728X variant in TG has not been previously reported in individuals with disease and was not identified in large population studies. This nonsense variant leads to a premature termination codon at position 1728 which is predicted to lead to a truncated or absent protein. Loss of function of TG has been established as a disease mechanism in congenital hypothyroidism. In summary, the Cys1728X variant in TG meets our criteria to be classified as pathogenic for congenital hypothyroidism in a recessive manner (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 17, 2024This sequence change creates a premature translational stop signal (p.Cys1728*) 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 (rs199599591, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with thyroid dyshormonogenesis (PMID: 31980526). ClinVar contains an entry for this variant (Variation ID: 208619). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.57
Cadd
Pathogenic
29
Dann
Uncertain
0.99
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.0050
FATHMM_MKL
Benign
0.52
D
MutationTaster
Benign
1.0
A;A
Vest4
0.87
GERP RS
3.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199599591; hg19: chr8-133953738; API