rs853326

Positions:

chr8-132897729-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

TG (HGNC:):

TG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr8-132897729-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TG	NM_003235.5 linkuse as main transcript	c.3082A>G	p.Met1028Val	missense_variant	12/48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.3082A>G	p.Met1028Val	missense_variant	12/48	1	NM_003235.5	ENSP00000220616.4	P01266-1
TG	ENST00000523756.5 linkuse as main transcript	n.40A>G		non_coding_transcript_exon_variant	1/35	1		ENSP00000428628.1	H0YB42
TG	ENST00000518505.1 linkuse as main transcript	c.-21A>G		upstream_gene_variant		4		ENSP00000429605.1	H0YBJ2
TG	ENST00000518097.1 linkuse as main transcript	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

GnomAD3 exomes

AF:

0.582

AC:

146257

AN:

251450

Hom.:

43426

AF XY:

0.582

AC XY:

79143

AN XY:

135908

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 SAS exome

AF:

0.645

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

Gnomad4 AFR exome

AF:

0.722

Gnomad4 AMR exome

AF:

0.562

Gnomad4 ASJ exome

AF:

0.611

Gnomad4 EAS exome

AF:

0.759

Gnomad4 SAS exome

AF:

0.648

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.508

Gnomad4 OTH exome

AF:

0.560

GnomAD4 genome

AF:

0.605

AC:

91943

AN:

152056

Hom.:

28447

Cov.:

AF XY:

0.612

AC XY:

45473

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.719

Gnomad4 AMR

AF:

0.597

Gnomad4 ASJ

AF:

0.618

Gnomad4 EAS

AF:

0.764

Gnomad4 SAS

AF:

0.659

Gnomad4 FIN

AF:

0.599

Gnomad4 NFE

AF:

0.522

Gnomad4 OTH

AF:

0.586

Alfa

AF:

0.546

Hom.:

56573

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Iodotyrosyl coupling defect

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Autoimmune thyroid disease, susceptibility to, 3

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

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

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

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

Varity_R

0.067

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over