rs180222

Positions:

chr8-132886915-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003235.5(TG):c.1543C>G(p.Gln515Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,030 control chromosomes in the GnomAD database, including 378 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.016 ( 25 hom., cov: 32)

Exomes 𝑓: 0.019 ( 353 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0870

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004487753).

BP6

Variant 8-132886915-C-G is Benign according to our data. Variant chr8-132886915-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258988.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr8-132886915-C-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0518 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.1543C>G	p.Gln515Glu	missense_variant	9/48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.1543C>G	p.Gln515Glu	missense_variant	9/48	1	NM_003235.5	ENSP00000220616.4		P01266-1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2414

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00541

Gnomad AMI

AF:

0.0703

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0163

AC:

4098

AN:

250794

Hom.:

AF XY:

0.0170

AC XY:

2309

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00563

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0187

AC:

27403

AN:

1461836

Hom.:

353

Cov.:

AF XY:

0.0190

AC XY:

13795

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00618

Gnomad4 AMR exome

AF:

0.0130

Gnomad4 ASJ exome

AF:

0.0306

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0103

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0204

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0159

AC:

2415

AN:

152194

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1151

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00542

Gnomad4 AMR

AF:

0.0166

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00913

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.0225

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0222

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0163

AC:

1979

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0272

EpiControl

AF:

0.0249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Iodotyrosyl coupling defect

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.045

DANN

Benign

0.15

DEOGEN2

Benign

0.019

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.27

REVEL

Benign

0.092

Sift

Benign

0.53

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.039

MPC

0.075

ClinPred

0.0023

GERP RS

-1.8

Varity_R

0.032

gMVP

0.14

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