8-132868141-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003235.5(TG):​c.94C>T​(p.Arg32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,614,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

TG
NM_003235.5 missense

Scores

5
12
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGNM_003235.5 linkuse as main transcriptc.94C>T p.Arg32Cys missense_variant 2/48 ENST00000220616.9 NP_003226.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGENST00000220616.9 linkuse as main transcriptc.94C>T p.Arg32Cys missense_variant 2/481 NM_003235.5 ENSP00000220616 P1P01266-1
TGENST00000523901.1 linkuse as main transcriptc.94C>T p.Arg32Cys missense_variant, NMD_transcript_variant 2/65 ENSP00000427871

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251420
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000229
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000338
AC:
494
AN:
1461878
Hom.:
1
Cov.:
32
AF XY:
0.000300
AC XY:
218
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000425
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000121
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Iodotyrosyl coupling defect Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.48
T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Uncertain
0.022
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.5
D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.87
MVP
0.82
MPC
0.48
ClinPred
0.69
D
GERP RS
5.4
Varity_R
0.42
gMVP
0.83

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: rs371315184; hg19: chr8-133880386; COSMIC: COSV99603910; API