rs2261147

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.3848-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 1,611,638 control chromosomes in the GnomAD database, including 291,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 21033 hom., cov: 32)

Exomes 𝑓: 0.60 ( 270496 hom. )

Consequence

TG
NM_003235.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.838

Publications

10 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 (BayesDel_noAF=-0.63).

BP6

Variant 8-132908166-T-C is Benign according to our data. Variant chr8-132908166-T-C is described in ClinVar as Benign. ClinVar VariationId is 258992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.3848-20T>C		intron_variant	Intron 17 of 47	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 link	c.3848-20T>C		intron_variant	Intron 17 of 47	1	NM_003235.5	ENSP00000220616.4		P01266-1
TG	ENST00000523756.5 link	n.*61-20T>C		intron_variant	Intron 4 of 34	1		ENSP00000428628.1		H0YB42

Frequencies

GnomAD3 genomes

AF:

0.481

AC:

73043

AN:

151812

Hom.:

21030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.357

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.693

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.507

GnomAD2 exomes

AF:

0.577

AC:

144436

AN:

250176

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:

0.699

Gnomad NFE exome

AF:

0.624

Gnomad OTH exome

AF:

0.600

GnomAD4 exome

AF:

0.601

AC:

877469

AN:

1459708

Hom.:

270496

Cov.:

AF XY:

0.601

AC XY:

436790

AN XY:

726258

show subpopulations

African (AFR)

AF:

0.136

AC:

4556

AN:

33466

American (AMR)

AF:

0.663

AC:

29652

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

14412

AN:

26126

East Asian (EAS)

AF:

0.363

AC:

14414

AN:

39666

South Asian (SAS)

AF:

0.580

AC:

49977

AN:

86204

European-Finnish (FIN)

AF:

0.701

AC:

36926

AN:

52662

Middle Eastern (MID)

AF:

0.550

AC:

3171

AN:

5766

European-Non Finnish (NFE)

AF:

0.622

AC:

690468

AN:

1110782

Other (OTH)

AF:

0.562

AC:

33893

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

18376

36752

55129

73505

91881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18262

36524

54786

73048

91310

<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:

0.481

AC:

73051

AN:

151930

Hom.:

21033

Cov.:

AF XY:

0.486

AC XY:

36087

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.152

AC:

6313

AN:

41518

American (AMR)

AF:

0.586

AC:

8941

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1896

AN:

3470

East Asian (EAS)

AF:

0.357

AC:

1834

AN:

5138

South Asian (SAS)

AF:

0.549

AC:

2639

AN:

4808

European-Finnish (FIN)

AF:

0.693

AC:

7318

AN:

10558

Middle Eastern (MID)

AF:

0.558

AC:

163

AN:

292

European-Non Finnish (NFE)

AF:

0.623

AC:

42270

AN:

67874

Other (OTH)

AF:

0.500

AC:

1052

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1402

2804

4207

5609

7011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.537

Hom.:

4280

Bravo

AF:

0.460

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

- -

Iodotyrosyl coupling defect

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.84

Mutation Taster

=100/0

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