rs2069561

Positions:

chr8-132963038-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.5512G>A(p.Asp1838Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,613,286 control chromosomes in the GnomAD database, including 210,810 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 0.40 ( 14939 hom., cov: 32)

Exomes 𝑓: 0.51 ( 195871 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.551

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=1.5006859E-5).

BP6

Variant 8-132963038-G-A is Benign according to our data. Variant chr8-132963038-G-A is described in ClinVar as [Benign]. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132963038-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 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.5512G>A	p.Asp1838Asn	missense_variant	29/48	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.5512G>A	p.Asp1838Asn	missense_variant	29/48	1	NM_003235.5	ENSP00000220616	P1	P01266-1
TG	ENST00000518058.1 linkuse as main transcript	c.46G>A	p.Asp16Asn	missense_variant	1/2	1		ENSP00000429164
TG	ENST00000523756.5 linkuse as main transcript	c.*1725G>A		3_prime_UTR_variant, NMD_transcript_variant	16/35	1		ENSP00000428628
TG	ENST00000519178.5 linkuse as main transcript	c.880G>A	p.Asp294Asn	missense_variant	8/27	2		ENSP00000430523

Frequencies

GnomAD3 genomes

AF:

0.402

AC:

60999

AN:

151890

Hom.:

14938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.480

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.349

Gnomad SAS

AF:

0.484

Gnomad FIN

AF:

0.583

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.516

Gnomad OTH

AF:

0.429

GnomAD3 exomes

AF:

0.495

AC:

124497

AN:

251260

Hom.:

32989

AF XY:

0.499

AC XY:

67688

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.0938

Gnomad AMR exome

AF:

0.632

Gnomad ASJ exome

AF:

0.488

Gnomad EAS exome

AF:

0.354

Gnomad SAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.576

Gnomad NFE exome

AF:

0.516

Gnomad OTH exome

AF:

0.508

GnomAD4 exome

AF:

0.511

AC:

747173

AN:

1461278

Hom.:

195871

Cov.:

AF XY:

0.511

AC XY:

371710

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0898

Gnomad4 AMR exome

AF:

0.617

Gnomad4 ASJ exome

AF:

0.489

Gnomad4 EAS exome

AF:

0.365

Gnomad4 SAS exome

AF:

0.507

Gnomad4 FIN exome

AF:

0.577

Gnomad4 NFE exome

AF:

0.525

Gnomad4 OTH exome

AF:

0.480

GnomAD4 genome

AF:

0.401

AC:

60995

AN:

152008

Hom.:

14939

Cov.:

AF XY:

0.406

AC XY:

30180

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.525

Gnomad4 ASJ

AF:

0.482

Gnomad4 EAS

AF:

0.349

Gnomad4 SAS

AF:

0.485

Gnomad4 FIN

AF:

0.583

Gnomad4 NFE

AF:

0.516

Gnomad4 OTH

AF:

0.422

Alfa

AF:

0.492

Hom.:

45859

Bravo

AF:

0.385

TwinsUK

AF:

0.535

AC:

1984

ALSPAC

AF:

0.538

AC:

2073

ESP6500AA

AF:

0.120

AC:

530

ESP6500EA

AF:

0.511

AC:

4398

ExAC

AF:

0.484

AC:

58829

Asia WGS

AF:

0.413

AC:

1438

AN:

3478

EpiCase

AF:

0.510

EpiControl

AF:

0.501

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	Feb 08, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 12, 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

0.083

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.2

DANN

Benign

0.94

DEOGEN2

Benign

0.048

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.47

MetaRNN

Benign

0.000015

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.84

REVEL

Benign

0.089

Sift

Benign

0.050

Sift4G

Benign

0.35

Polyphen

0.0010

Vest4

0.026

MPC

0.068

ClinPred

0.011

GERP RS

1.7

Varity_R

0.067

gMVP

0.18

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