rs121912647

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_003235.5(TG):​c.3733T>C​(p.Cys1245Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

TG
NM_003235.5 missense

Scores

9
8
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.45
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 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
Variant 8-132906786-T-C is Pathogenic according to our data. Variant chr8-132906786-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12693.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGNM_003235.5 linkuse as main transcriptc.3733T>C p.Cys1245Arg missense_variant 17/48 ENST00000220616.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGENST00000220616.9 linkuse as main transcriptc.3733T>C p.Cys1245Arg missense_variant 17/481 NM_003235.5 P1P01266-1
TGENST00000523756.5 linkuse as main transcriptc.390T>C p.Ser130= synonymous_variant, NMD_transcript_variant 4/351
TGENST00000518505.1 linkuse as main transcriptc.565T>C p.Cys189Arg missense_variant 6/64

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

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 providedliterature onlyOMIMAug 01, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.68
T
M_CAP
Uncertain
0.098
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.77
Gain of disorder (P = 0.0223);
MVP
0.90
MPC
0.54
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.97
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs121912647; hg19: chr8-133919031; API