rs2076740

chr8-132971813-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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 NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.149

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]

ACMG classification

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	UniProt
TG	NM_003235.5	c.5995C>T	p.Arg1999Trp	missense_variant	33/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.5995C>T	p.Arg1999Trp	missense_variant	33/48	1	NM_003235.5	P1

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

GnomAD3 exomes AF: 0.314 AC: 78777 AN: 251218 Hom.: 13343 AF XY: 0.315 AC XY: 42755 AN XY: 135770

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

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.: 32 AF XY: 0.364 AC XY: 27039 AN XY: 74284

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2019	This variant is associated with the following publications: (PMID: 14657345) -

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	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
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.00080	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

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