chr8-132967797-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003235.5(TG):​c.5690G>A​(p.Cys1897Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,440 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TG
NM_003235.5 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.58
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGNM_003235.5 linkuse as main transcriptc.5690G>A p.Cys1897Tyr missense_variant 31/48 ENST00000220616.9 NP_003226.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGENST00000220616.9 linkuse as main transcriptc.5690G>A p.Cys1897Tyr missense_variant 31/481 NM_003235.5 ENSP00000220616 P1P01266-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461440
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727036
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00152
Hom.:
0

ClinVar

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

Submissions by phenotype

Iodotyrosyl coupling defect Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2006- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 08, 2022Identified with a second TG variant likely on the opposite allele (in trans) in a patient with congenital goitrous hypothyroidism (Hishinuma et al., 2006; Kitanaka et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as C1878Y; This variant is associated with the following publications: (PMID: 16477365, 16720658) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.032
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Pathogenic
3.0
M;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.92
Gain of helix (P = 0.132);.;
MVP
0.91
MPC
0.53
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.91
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs121912649; hg19: chr8-133980042; API