rs853326

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.3082A>G(p.Met1028Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,880 control chromosomes in the GnomAD database, including 242,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 28447 hom., cov: 33)

Exomes 𝑓: 0.54 ( 213884 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.416

Publications

47 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=2.1309193E-6).

BP6

Variant 8-132897729-A-G is Benign according to our data. Variant chr8-132897729-A-G is described in ClinVar as [Benign]. Clinvar id is 12698.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.3082A>G	p.Met1028Val	missense_variant	Exon 12 of 48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TG	ENST00000220616.9 link	c.3082A>G	p.Met1028Val	missense_variant	Exon 12 of 48	1	NM_003235.5	ENSP00000220616.4	P01266-1
TG	ENST00000523756.5 link	n.40A>G		non_coding_transcript_exon_variant	Exon 1 of 35	1		ENSP00000428628.1	H0YB42
TG	ENST00000518505.1 link	c.-21A>G		upstream_gene_variant		4		ENSP00000429605.1	H0YBJ2
TG	ENST00000518097.1 link	n.-5A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91854

AN:

151938

Hom.:

28408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.718

Gnomad AMI

AF:

0.589

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.763

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.593

GnomAD2 exomes

AF:

0.582

AC:

146257

AN:

251450

AF XY:

0.582

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.762

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.522

Gnomad OTH exome

AF:

0.576

GnomAD4 exome

AF:

0.537

AC:

784336

AN:

1461824

Hom.:

213884

Cov.:

AF XY:

0.540

AC XY:

392555

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.722

AC:

24178

AN:

33480

American (AMR)

AF:

0.562

AC:

25127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.611

AC:

15972

AN:

26136

East Asian (EAS)

AF:

0.759

AC:

30134

AN:

39700

South Asian (SAS)

AF:

0.648

AC:

55929

AN:

86258

European-Finnish (FIN)

AF:

0.579

AC:

30933

AN:

53414

Middle Eastern (MID)

AF:

0.606

AC:

3495

AN:

5768

European-Non Finnish (NFE)

AF:

0.508

AC:

564743

AN:

1111952

Other (OTH)

AF:

0.560

AC:

33825

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23375

46750

70126

93501

116876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.605

AC:

91943

AN:

152056

Hom.:

28447

Cov.:

AF XY:

0.612

AC XY:

45473

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.719

AC:

29807

AN:

41472

American (AMR)

AF:

0.597

AC:

9135

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2143

AN:

3468

East Asian (EAS)

AF:

0.764

AC:

3934

AN:

5152

South Asian (SAS)

AF:

0.659

AC:

3180

AN:

4828

European-Finnish (FIN)

AF:

0.599

AC:

6326

AN:

10562

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35475

AN:

67954

Other (OTH)

AF:

0.586

AC:

1239

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1840

3679

5519

7358

9198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.555

Hom.:

81656

Bravo

AF:

0.609

TwinsUK

AF:

0.507

AC:

1879

ALSPAC

AF:

0.518

AC:

1998

ESP6500AA

AF:

0.727

AC:

3205

ESP6500EA

AF:

0.518

AC:

4451

ExAC

AF:

0.584

AC:

70901

Asia WGS

AF:

0.681

AC:

2368

AN:

3478

EpiCase

AF:

0.535

EpiControl

AF:

0.535

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

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

- -

Mar 24, 2020

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

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0040

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.016

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.054

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

PhyloP100

-0.42

PrimateAI

Benign

0.33

PROVEAN

Benign

0.83

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.020

MPC

0.070

ClinPred

0.0013

GERP RS

-0.44

PromoterAI

0.017

Neutral

(source)

Varity_R

0.067

gMVP

0.31

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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rs853326

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