rs56230101

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003235.5(TG):c.5921T>C(p.Met1974Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,613,072 control chromosomes in the GnomAD database, including 7,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2088 hom., cov: 31)

Exomes 𝑓: 0.073 ( 5126 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.818

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]

TG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054279864).

BP6

Variant 8-132969515-T-C is Benign according to our data. Variant chr8-132969515-T-C is described in ClinVar as [Benign]. Clinvar id is 258997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132969515-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5 linkuse as main transcript	c.5921T>C	p.Met1974Thr	missense_variant	32/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.5921T>C	p.Met1974Thr	missense_variant	32/48	1	NM_003235.5	P1	P01266-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19610

AN:

151990

Hom.:

2072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0787

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0684

Gnomad FIN

AF:

0.0678

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0695

Gnomad OTH

AF:

0.123

GnomAD3 exomes

AF:

0.0789

AC:

19824

AN:

251396

Hom.:

1270

AF XY:

0.0777

AC XY:

10554

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.301

Gnomad AMR exome

AF:

0.0443

Gnomad ASJ exome

AF:

0.0855

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0777

Gnomad FIN exome

AF:

0.0665

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0838

GnomAD4 exome

AF:

0.0730

AC:

106676

AN:

1460962

Hom.:

5126

Cov.:

AF XY:

0.0726

AC XY:

52772

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.306

Gnomad4 AMR exome

AF:

0.0479

Gnomad4 ASJ exome

AF:

0.0816

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0781

Gnomad4 FIN exome

AF:

0.0684

Gnomad4 NFE exome

AF:

0.0687

Gnomad4 OTH exome

AF:

0.0807

GnomAD4 genome

AF:

0.129

AC:

19661

AN:

152110

Hom.:

2088

Cov.:

AF XY:

0.126

AC XY:

9348

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.295

Gnomad4 AMR

AF:

0.0714

Gnomad4 ASJ

AF:

0.0787

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0684

Gnomad4 FIN

AF:

0.0678

Gnomad4 NFE

AF:

0.0695

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.0803

Hom.:

1152

Bravo

AF:

0.137

TwinsUK

AF:

0.0669

AC:

248

ALSPAC

AF:

0.0664

AC:

256

ESP6500AA

AF:

0.290

AC:

1278

ESP6500EA

AF:

0.0736

AC:

633

ExAC

AF:

0.0842

AC:

10220

Asia WGS

AF:

0.0440

AC:

153

AN:

3478

EpiCase

AF:

0.0721

EpiControl

AF:

0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Iodotyrosyl coupling defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.021

DANN

Benign

0.18

DEOGEN2

Benign

0.032

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.069

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.22

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.074

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.024

MPC

0.078

ClinPred

0.0030

GERP RS

-0.078

Varity_R

0.13

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over