chr8-133131869-C-T

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.7920C>T(p.Tyr2640Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,812 control chromosomes in the GnomAD database, including 180,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18754 hom., cov: 32)

Exomes 𝑓: 0.46 ( 161925 hom. )

Consequence

TG
NM_003235.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.250

Publications

14 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 (BayesDel_noAF=-0.69).

BP6

Variant 8-133131869-C-T is Benign according to our data. Variant chr8-133131869-C-T is described in ClinVar as Benign. ClinVar VariationId is 259003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.7920C>T	p.Tyr2640Tyr	synonymous_variant	Exon 46 of 48	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.7920C>T	p.Tyr2640Tyr	synonymous_variant	Exon 46 of 48	1	NM_003235.5	ENSP00000220616.4		P01266-1

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

73948

AN:

151878

Hom.:

18735

Cov.:

show subpopulations

Gnomad AFR

AF:

0.583

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.452

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.378

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.508

GnomAD2 exomes

AF:

0.428

AC:

107635

AN:

251420

AF XY:

0.425

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.385

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.458

GnomAD4 exome

AF:

0.464

AC:

677945

AN:

1461816

Hom.:

161925

Cov.:

AF XY:

0.460

AC XY:

334335

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.591

AC:

19789

AN:

33480

American (AMR)

AF:

0.401

AC:

17913

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.555

AC:

14514

AN:

26136

East Asian (EAS)

AF:

0.129

AC:

5130

AN:

39700

South Asian (SAS)

AF:

0.321

AC:

27720

AN:

86256

European-Finnish (FIN)

AF:

0.394

AC:

21042

AN:

53416

Middle Eastern (MID)

AF:

0.522

AC:

3011

AN:

5766

European-Non Finnish (NFE)

AF:

0.486

AC:

540380

AN:

1111946

Other (OTH)

AF:

0.471

AC:

28446

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

21736

43473

65209

86946

108682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15704

31408

47112

62816

78520

<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:

0.487

AC:

73999

AN:

151996

Hom.:

18754

Cov.:

AF XY:

0.475

AC XY:

35323

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.583

AC:

24181

AN:

41450

American (AMR)

AF:

0.451

AC:

6895

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.567

AC:

1966

AN:

3470

East Asian (EAS)

AF:

0.164

AC:

847

AN:

5160

South Asian (SAS)

AF:

0.309

AC:

1488

AN:

4812

European-Finnish (FIN)

AF:

0.378

AC:

3983

AN:

10544

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.487

AC:

33090

AN:

67976

Other (OTH)

AF:

0.503

AC:

1060

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1869

3738

5606

7475

9344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.467

Hom.:

48471

Bravo

AF:

0.497

Asia WGS

AF:

0.239

AC:

830

AN:

3476

EpiCase

AF:

0.489

EpiControl

AF:

0.489

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2021

GeneDx

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

- -

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 specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.69

CADD

Benign

5.6

(source)

DANN

Benign

0.47

PhyloP100

-0.25

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