rs2069556

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

27 publications found

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 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

TG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 258993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Ensembl

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

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

GnomAD2 exomes

AF:

0.578

AC:

145164

AN:

251308

AF XY:

0.584

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 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

African (AFR)

AF:

0.136

AC:

4561

AN:

33480

American (AMR)

AF:

0.663

AC:

29657

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

14413

AN:

26126

East Asian (EAS)

AF:

0.363

AC:

14420

AN:

39678

South Asian (SAS)

AF:

0.580

AC:

50008

AN:

86256

European-Finnish (FIN)

AF:

0.702

AC:

37385

AN:

53280

Middle Eastern (MID)

AF:

0.550

AC:

3171

AN:

5766

European-Non Finnish (NFE)

AF:

0.622

AC:

690904

AN:

1111642

Other (OTH)

AF:

0.562

AC:

33902

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

21730

43459

65189

86918

108648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18286

36572

54858

73144

91430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.479

AC:

72194

AN:

150702

Hom.:

20792

Cov.:

AF XY:

0.484

AC XY:

35579

AN XY:

73556

show subpopulations

African (AFR)

AF:

0.150

AC:

6207

AN:

41314

American (AMR)

AF:

0.584

AC:

8799

AN:

15056

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1880

AN:

3442

East Asian (EAS)

AF:

0.351

AC:

1766

AN:

5030

South Asian (SAS)

AF:

0.547

AC:

2577

AN:

4714

European-Finnish (FIN)

AF:

0.691

AC:

7174

AN:

10386

Middle Eastern (MID)

AF:

0.558

AC:

163

AN:

292

European-Non Finnish (NFE)

AF:

0.622

AC:

41976

AN:

67486

Other (OTH)

AF:

0.498

AC:

1038

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

1471

2942

4413

5884

7355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

632

1264

1896

2528

3160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.576

Hom.:

98785

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

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Iodotyrosyl coupling defect

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

4.8

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over