chr8-133113438-G-A

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.7589G>A(p.Arg2530Gln) variant causes a missense change. The variant allele was found at a frequency of 0.491 in 1,613,204 control chromosomes in the GnomAD database, including 200,372 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 0.56 ( 25216 hom., cov: 29)

Exomes 𝑓: 0.48 ( 175156 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.12

Publications

36 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=1.1719324E-6).

BP6

Variant 8-133113438-G-A is Benign according to our data. Variant chr8-133113438-G-A is described in ClinVar as Benign. ClinVar VariationId is 259002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.7589G>A	p.Arg2530Gln	missense_variant	Exon 44 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.7589G>A	p.Arg2530Gln	missense_variant	Exon 44 of 48	1	NM_003235.5	ENSP00000220616.4		P01266-1

Frequencies

GnomAD3 genomes

AF:

0.557

AC:

84277

AN:

151426

Hom.:

25174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.497

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.478

Gnomad NFE

AF:

0.481

Gnomad OTH

AF:

0.522

GnomAD2 exomes

AF:

0.485

AC:

121755

AN:

251276

AF XY:

0.485

show subpopulations

Gnomad AFR exome

AF:

0.788

Gnomad AMR exome

AF:

0.325

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.390

Gnomad FIN exome

AF:

0.576

Gnomad NFE exome

AF:

0.484

Gnomad OTH exome

AF:

0.478

GnomAD4 exome

AF:

0.485

AC:

708354

AN:

1461658

Hom.:

175156

Cov.:

AF XY:

0.485

AC XY:

352372

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.793

AC:

26537

AN:

33476

American (AMR)

AF:

0.334

AC:

14924

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

12275

AN:

26136

East Asian (EAS)

AF:

0.357

AC:

14177

AN:

39696

South Asian (SAS)

AF:

0.500

AC:

43106

AN:

86252

European-Finnish (FIN)

AF:

0.572

AC:

30549

AN:

53396

Middle Eastern (MID)

AF:

0.520

AC:

2998

AN:

5766

European-Non Finnish (NFE)

AF:

0.480

AC:

533915

AN:

1111824

Other (OTH)

AF:

0.495

AC:

29873

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

20760

41519

62279

83038

103798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15736

31472

47208

62944

78680

<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:

0.557

AC:

84369

AN:

151546

Hom.:

25216

Cov.:

AF XY:

0.555

AC XY:

41073

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.780

AC:

32216

AN:

41320

American (AMR)

AF:

0.383

AC:

5840

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.451

AC:

1560

AN:

3462

East Asian (EAS)

AF:

0.394

AC:

2024

AN:

5136

South Asian (SAS)

AF:

0.497

AC:

2371

AN:

4772

European-Finnish (FIN)

AF:

0.577

AC:

6036

AN:

10470

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.481

AC:

32652

AN:

67848

Other (OTH)

AF:

0.518

AC:

1088

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1708

3416

5125

6833

8541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.495

Hom.:

94360

Bravo

AF:

0.550

TwinsUK

AF:

0.490

AC:

1817

ALSPAC

AF:

0.471

AC:

1814

ESP6500AA

AF:

0.769

AC:

3390

ESP6500EA

AF:

0.474

AC:

4078

ExAC

AF:

0.497

AC:

60352

Asia WGS

AF:

0.429

AC:

1496

AN:

3476

EpiCase

AF:

0.476

EpiControl

AF:

0.476

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14633662) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Iodotyrosyl coupling defect

Benign:2

Mar 06, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.058

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.6

N;.

PhyloP100

5.1

PrimateAI

Benign

0.47

PROVEAN

Benign

2.7

N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0040

B;B

Vest4

0.16

MPC

0.078

ClinPred

0.011

GERP RS

4.8

PromoterAI

0.0028

Neutral

(source)

Varity_R

0.065

gMVP

0.40

Mutation Taster

=99/1

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