rs2069556

Variant names:

Variant summary

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

The NM_003235.5(TG):c.3935A>G(p.Asp1312Gly) variant causes a missense change. The variant allele was found at a frequency of 0.59 in 1,611,998 control chromosomes in the GnomAD database, including 291,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 20792 hom., cov: 28)

Exomes 𝑓: 0.60 ( 270677 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.83

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=4.33528E-6).

BP6

Variant 8-132908273-A-G is Benign according to our data. Variant chr8-132908273-A-G is described in ClinVar as [Benign]. Clinvar id is 258993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132908273-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.3935A>G	p.Asp1312Gly	missense_variant	Exon 18 of 48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TG	ENST00000220616.9 link	c.3935A>G	p.Asp1312Gly	missense_variant	Exon 18 of 48	1	NM_003235.5	ENSP00000220616.4	P01266-1
TG	ENST00000523756.5 link	n.*148A>G		non_coding_transcript_exon_variant	Exon 5 of 35	1		ENSP00000428628.1	H0YB42
TG	ENST00000523756.5 link	n.*148A>G		3_prime_UTR_variant	Exon 5 of 35	1		ENSP00000428628.1	H0YB42

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72184

AN:

150582

Hom.:

20788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.685

Gnomad AMR

AF:

0.584

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.351

Gnomad SAS

AF:

0.546

Gnomad FIN

AF:

0.691

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.505

GnomAD3 exomes

AF:

0.578

AC:

145164

AN:

251308

Hom.:

44576

AF XY:

0.584

AC XY:

79320

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.676

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.364

Gnomad SAS exome

AF:

0.577

Gnomad FIN exome

AF:

0.700

Gnomad NFE exome

AF:

0.624

Gnomad OTH exome

AF:

0.601

GnomAD4 exome

AF:

0.601

AC:

878421

AN:

1461296

Hom.:

270677

Cov.:

AF XY:

0.601

AC XY:

437221

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.663

Gnomad4 ASJ exome

AF:

0.552

Gnomad4 EAS exome

AF:

0.363

Gnomad4 SAS exome

AF:

0.580

Gnomad4 FIN exome

AF:

0.702

Gnomad4 NFE exome

AF:

0.622

Gnomad4 OTH exome

AF:

0.562

GnomAD4 genome

AF:

0.479

AC:

72194

AN:

150702

Hom.:

20792

Cov.:

AF XY:

0.484

AC XY:

35579

AN XY:

73556

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.584

Gnomad4 ASJ

AF:

0.546

Gnomad4 EAS

AF:

0.351

Gnomad4 SAS

AF:

0.547

Gnomad4 FIN

AF:

0.691

Gnomad4 NFE

AF:

0.622

Gnomad4 OTH

AF:

0.498

Alfa

AF:

0.586

Hom.:

52927

Bravo

AF:

0.459

TwinsUK

AF:

0.622

AC:

2305

ALSPAC

AF:

0.636

AC:

2451

ESP6500AA

AF:

0.162

AC:

714

ESP6500EA

AF:

0.615

AC:

5290

ExAC

AF:

0.570

AC:

69139

EpiCase

AF:

0.613

EpiControl

AF:

0.610

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Iodotyrosyl coupling defect

Benign:2

Jan 13, 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 provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.16

DEOGEN2

Benign

0.053

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0000043

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.1

PrimateAI

Benign

0.36

PROVEAN

Benign

2.8

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.070

MPC

0.089

ClinPred

0.0050

GERP RS

5.5

Varity_R

0.21

gMVP

0.36

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