rs1133076

Positions:

chr8-133113438-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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:

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=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 id is 259002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133113438-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TG	NM_003235.5 linkuse as main transcript	c.7589G>A	p.Arg2530Gln	missense_variant	44/48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.7589G>A	p.Arg2530Gln	missense_variant	44/48	1	NM_003235.5	ENSP00000220616	P1	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

GnomAD3 exomes

AF:

0.485

AC:

121755

AN:

251276

Hom.:

31018

AF XY:

0.485

AC XY:

65892

AN XY:

135816

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 SAS exome

AF:

0.503

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

Gnomad4 AFR exome

AF:

0.793

Gnomad4 AMR exome

AF:

0.334

Gnomad4 ASJ exome

AF:

0.470

Gnomad4 EAS exome

AF:

0.357

Gnomad4 SAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.480

Gnomad4 OTH exome

AF:

0.495

GnomAD4 genome

AF:

0.557

AC:

84369

AN:

151546

Hom.:

25216

Cov.:

AF XY:

0.555

AC XY:

41073

AN XY:

74038

show subpopulations

Gnomad4 AFR

AF:

0.780

Gnomad4 AMR

AF:

0.383

Gnomad4 ASJ

AF:

0.451

Gnomad4 EAS

AF:

0.394

Gnomad4 SAS

AF:

0.497

Gnomad4 FIN

AF:

0.577

Gnomad4 NFE

AF:

0.481

Gnomad4 OTH

AF:

0.518

Alfa

AF:

0.484

Hom.:

45255

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

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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 14633662) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Mar 06, 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. -

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

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;.

MutationTaster

Benign

1.0

P;P;P

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

Varity_R

0.065

gMVP

0.40

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