rs2076740

Positions:

chr8-132971813-C-T

Variant summary

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

The ENST00000220616.9(TG):c.5995C>T(p.Arg1999Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,610,356 control chromosomes in the GnomAD database, including 93,906 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1999R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.37 ( 11063 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82843 hom. )

Consequence

TG
ENST00000220616.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.149

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=7.983446E-4).

BP6

Variant 8-132971813-C-T is Benign according to our data. Variant chr8-132971813-C-T is described in ClinVar as [Benign]. Clinvar id is 12696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132971813-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TG	NM_003235.5 linkuse as main transcript	c.5995C>T	p.Arg1999Trp	missense_variant	33/48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.5995C>T	p.Arg1999Trp	missense_variant	33/48	1	NM_003235.5	ENSP00000220616	P1	P01266-1

Frequencies

GnomAD3 genomes

AF:

0.369

AC:

56076

AN:

151882

Hom.:

11058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.443

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.345

Gnomad OTH

AF:

0.366

GnomAD3 exomes

AF:

0.314

AC:

78777

AN:

251218

Hom.:

13343

AF XY:

0.315

AC XY:

42755

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.406

Gnomad EAS exome

AF:

0.170

Gnomad SAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.346

Gnomad OTH exome

AF:

0.331

GnomAD4 exome

AF:

0.333

AC:

485422

AN:

1458356

Hom.:

82843

Cov.:

AF XY:

0.332

AC XY:

241118

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.501

Gnomad4 AMR exome

AF:

0.202

Gnomad4 ASJ exome

AF:

0.412

Gnomad4 EAS exome

AF:

0.199

Gnomad4 SAS exome

AF:

0.278

Gnomad4 FIN exome

AF:

0.319

Gnomad4 NFE exome

AF:

0.340

Gnomad4 OTH exome

AF:

0.338

GnomAD4 genome

AF:

0.369

AC:

56101

AN:

152000

Hom.:

11063

Cov.:

AF XY:

0.364

AC XY:

27039

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.499

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.400

Gnomad4 EAS

AF:

0.177

Gnomad4 SAS

AF:

0.282

Gnomad4 FIN

AF:

0.316

Gnomad4 NFE

AF:

0.345

Gnomad4 OTH

AF:

0.362

Alfa

AF:

0.351

Hom.:

13539

Bravo

AF:

0.370

TwinsUK

AF:

0.334

AC:

1239

ALSPAC

AF:

0.338

AC:

1303

ESP6500AA

AF:

0.498

AC:

2194

ESP6500EA

AF:

0.337

AC:

2901

ExAC

AF:

0.323

AC:

39172

Asia WGS

AF:

0.242

AC:

846

AN:

3476

EpiCase

AF:

0.353

EpiControl

AF:

0.352

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2019	This variant is associated with the following publications: (PMID: 14657345) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Iodotyrosyl coupling defect

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autoimmune thyroid disease, susceptibility to, 3

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.4

DANN

Benign

0.94

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.00080

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.15

Sift

Benign

0.14

T;T

Sift4G

Uncertain

0.043

D;T

Polyphen

0.0050

B;B

Vest4

0.13

MPC

0.082

ClinPred

0.0054

GERP RS

-0.16

Varity_R

0.10

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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