rs2076740

Variant names:

• chr8-132971813-C-T
• rs2076740
• NM_003235.5:c.5995C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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 NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.149
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 12696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TG	NM_003235.5	c.5995C>T	p.Arg1999Trp	missense_variant	Exon 33 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.5995C>T	p.Arg1999Trp	missense_variant	Exon 33 of 48	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56076 AN: 151882 Hom.: 11058 Cov.: 32

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

GnomAD2 exomes AF: 0.314 AC: 78777 AN: 251218 AF XY: 0.315

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 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.: 32 AF XY: 0.332 AC XY: 241118 AN XY: 725660

African (AFR) AF: 0.501 AC: 16728 AN: 33386

American (AMR) AF: 0.202 AC: 9043 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10750 AN: 26122

East Asian (EAS) AF: 0.199 AC: 7904 AN: 39678

South Asian (SAS) AF: 0.278 AC: 23949 AN: 86184

European-Finnish (FIN) AF: 0.319 AC: 17040 AN: 53404

Middle Eastern (MID) AF: 0.381 AC: 2198 AN: 5762

European-Non Finnish (NFE) AF: 0.340 AC: 377441 AN: 1108844

Other (OTH) AF: 0.338 AC: 20369 AN: 60264

GnomAD4 genome AF: 0.369 AC: 56101 AN: 152000 Hom.: 11063 Cov.: 32 AF XY: 0.364 AC XY: 27039 AN XY: 74284

African (AFR) AF: 0.499 AC: 20671 AN: 41452

American (AMR) AF: 0.244 AC: 3725 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1386 AN: 3468

East Asian (EAS) AF: 0.177 AC: 912 AN: 5162

South Asian (SAS) AF: 0.282 AC: 1356 AN: 4814

European-Finnish (FIN) AF: 0.316 AC: 3337 AN: 10556

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23448 AN: 67962

Other (OTH) AF: 0.362 AC: 762 AN: 2106

Alfa AF: 0.353 Hom.: 34666

Bravo AF: 0.370

TwinsUK AF: 0.334 AC: 1239

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14657345)

Iodotyrosyl coupling defect Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autoimmune thyroid disease, susceptibility to, 3 Other:1

Dec 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
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
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.00080	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		0.15
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.47	N;N
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.043	D;T
Vest4		0.13
ClinPred		0.0054	T
GERP RS		-0.16
Varity_R		0.10
gMVP		0.57
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2076740; hg19: chr8-133984058; COSMIC: COSV55069765; COSMIC: COSV55069765;