NM_003235.5:c.2200T>G

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.2200T>G(p.Ser734Ala) variant causes a missense change. The variant allele was found at a frequency of 0.543 in 1,613,142 control chromosomes in the GnomAD database, including 242,273 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S734S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.61 ( 28498 hom., cov: 32)

Exomes 𝑓: 0.54 ( 213775 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 6.19

Publications

53 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=2.9808534E-6).

BP6

Variant 8-132888007-T-G is Benign according to our data. Variant chr8-132888007-T-G is described in ClinVar as Benign. ClinVar VariationId is 12697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.2200T>G	p.Ser734Ala	missense	Exon 10 of 48	NP_003226.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.2200T>G	p.Ser734Ala	missense	Exon 10 of 48	ENSP00000220616.4

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91918

AN:

151912

Hom.:

28460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.720

Gnomad AMI

AF:

0.588

Gnomad AMR

AF:

0.598

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.764

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.594

GnomAD2 exomes

AF:

0.582

AC:

145269

AN:

249816

AF XY:

0.582

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.607

Gnomad EAS exome

AF:

0.763

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.521

Gnomad OTH exome

AF:

0.575

GnomAD4 exome

AF:

0.537

AC:

783906

AN:

1461110

Hom.:

213775

Cov.:

AF XY:

0.540

AC XY:

392306

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.724

AC:

24225

AN:

33472

American (AMR)

AF:

0.562

AC:

25074

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.611

AC:

15961

AN:

26122

East Asian (EAS)

AF:

0.761

AC:

30213

AN:

39688

South Asian (SAS)

AF:

0.648

AC:

55848

AN:

86178

European-Finnish (FIN)

AF:

0.579

AC:

30905

AN:

53372

Middle Eastern (MID)

AF:

0.605

AC:

3490

AN:

5768

European-Non Finnish (NFE)

AF:

0.508

AC:

564368

AN:

1111514

Other (OTH)

AF:

0.560

AC:

33822

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

21486

42972

64458

85944

107430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16484

32968

49452

65936

82420

<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:

0.605

AC:

92006

AN:

152032

Hom.:

28498

Cov.:

AF XY:

0.612

AC XY:

45523

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.720

AC:

29883

AN:

41480

American (AMR)

AF:

0.598

AC:

9128

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2138

AN:

3460

East Asian (EAS)

AF:

0.764

AC:

3947

AN:

5164

South Asian (SAS)

AF:

0.658

AC:

3170

AN:

4814

European-Finnish (FIN)

AF:

0.599

AC:

6337

AN:

10572

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35462

AN:

67950

Other (OTH)

AF:

0.586

AC:

1239

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1810

3620

5429

7239

9049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.551

Hom.:

40552

Bravo

AF:

0.609

TwinsUK

AF:

0.507

AC:

1879

ALSPAC

AF:

0.518

AC:

1996

ESP6500AA

AF:

0.730

AC:

3216

ESP6500EA

AF:

0.517

AC:

4448

ExAC

AF:

0.583

AC:

70804

Asia WGS

AF:

0.678

AC:

2357

AN:

3478

EpiCase

AF:

0.535

EpiControl

AF:

0.535

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.051

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.041

MetaRNN

Benign

0.0000030

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

PhyloP100

6.2

PrimateAI

Benign

0.46

PROVEAN

Benign

1.3

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.041

MPC

0.059

ClinPred

0.0050

GERP RS

5.8

Varity_R

0.21

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over