8-132919503-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003235.5(TG):c.4506T>C(p.Ala1502Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,613,638 control chromosomes in the GnomAD database, including 296,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23954 hom., cov: 32)

Exomes 𝑓: 0.61 ( 272150 hom. )

Consequence

TG
NM_003235.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.297

Publications

15 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.014).

BP6

Variant 8-132919503-T-C is Benign according to our data. Variant chr8-132919503-T-C is described in ClinVar as Benign. ClinVar VariationId is 258994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.297 with no splicing effect.

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.4506T>C	p.Ala1502Ala	synonymous_variant	Exon 21 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TG	ENST00000220616.9 link	c.4506T>C	p.Ala1502Ala	synonymous_variant	Exon 21 of 48	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523756.5 link	n.*719T>C		non_coding_transcript_exon_variant	Exon 8 of 35	1		ENSP00000428628.1
TG	ENST00000523756.5 link	n.*719T>C		3_prime_UTR_variant	Exon 8 of 35	1		ENSP00000428628.1
TG	ENST00000519178.5 link	c.63T>C	p.Ala21Ala	synonymous_variant	Exon 1 of 27	2		ENSP00000430523.1

Frequencies

GnomAD3 genomes

AF:

0.550

AC:

83567

AN:

151934

Hom.:

23946

Cov.:

show subpopulations

Gnomad AFR

AF:

0.397

Gnomad AMI

AF:

0.620

Gnomad AMR

AF:

0.611

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.687

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.548

GnomAD2 exomes

AF:

0.595

AC:

149181

AN:

250886

AF XY:

0.596

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.609

GnomAD4 exome

AF:

0.606

AC:

886135

AN:

1461586

Hom.:

272150

Cov.:

AF XY:

0.606

AC XY:

440276

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.383

AC:

12827

AN:

33472

American (AMR)

AF:

0.677

AC:

30271

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

14415

AN:

26130

East Asian (EAS)

AF:

0.362

AC:

14380

AN:

39700

South Asian (SAS)

AF:

0.580

AC:

50021

AN:

86252

European-Finnish (FIN)

AF:

0.698

AC:

37260

AN:

53354

Middle Eastern (MID)

AF:

0.561

AC:

3220

AN:

5744

European-Non Finnish (NFE)

AF:

0.620

AC:

688927

AN:

1111838

Other (OTH)

AF:

0.577

AC:

34814

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

20814

41628

62441

83255

104069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18362

36724

55086

73448

91810

<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:

0.550

AC:

83600

AN:

152052

Hom.:

23954

Cov.:

AF XY:

0.552

AC XY:

41053

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.397

AC:

16460

AN:

41452

American (AMR)

AF:

0.612

AC:

9350

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1897

AN:

3472

East Asian (EAS)

AF:

0.358

AC:

1851

AN:

5168

South Asian (SAS)

AF:

0.549

AC:

2642

AN:

4816

European-Finnish (FIN)

AF:

0.687

AC:

7267

AN:

10572

Middle Eastern (MID)

AF:

0.565

AC:

165

AN:

292

European-Non Finnish (NFE)

AF:

0.622

AC:

42261

AN:

67964

Other (OTH)

AF:

0.540

AC:

1142

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1845

3690

5536

7381

9226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.596

Hom.:

23385

Bravo

AF:

0.537

Asia WGS

AF:

0.462

AC:

1610

AN:

3478

EpiCase

AF:

0.612

EpiControl

AF:

0.609

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

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

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.042

(source)

DANN

Benign

0.30

PhyloP100

-0.30

PromoterAI

0.044

Neutral

(source)

Mutation Taster

=98/2

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

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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