8-133012033-C-T

Position:

chr8-133012033-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000220616.9(TG):c.6395C>T(p.Ser2132Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,614,108 control chromosomes in the GnomAD database, including 2,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 177 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2440 hom. )

Consequence

TG
ENST00000220616.9 missense, splice_region

Scores

Splicing: ADA: 0.0003433

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.291

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=0.003029853).

BP6

Variant 8-133012033-C-T is Benign according to our data. Variant chr8-133012033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133012033-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0595 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.6395C>T	p.Ser2132Leu	missense_variant, splice_region_variant	36/48	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.6395C>T	p.Ser2132Leu	missense_variant, splice_region_variant	36/48	1	NM_003235.5	ENSP00000220616	P1	P01266-1

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6339

AN:

152136

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0365

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0505

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0611

Gnomad OTH

AF:

0.0473

GnomAD3 exomes

AF:

0.0451

AC:

11336

AN:

251266

Hom.:

350

AF XY:

0.0475

AC XY:

6448

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0238

Gnomad ASJ exome

AF:

0.0417

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0493

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.0611

Gnomad OTH exome

AF:

0.0561

GnomAD4 exome

AF:

0.0545

AC:

79741

AN:

1461854

Hom.:

2440

Cov.:

AF XY:

0.0550

AC XY:

40023

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

Gnomad4 AMR exome

AF:

0.0253

Gnomad4 ASJ exome

AF:

0.0432

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0517

Gnomad4 FIN exome

AF:

0.0507

Gnomad4 NFE exome

AF:

0.0597

Gnomad4 OTH exome

AF:

0.0511

GnomAD4 genome

AF:

0.0417

AC:

6343

AN:

152254

Hom.:

177

Cov.:

AF XY:

0.0406

AC XY:

3025

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.0365

Gnomad4 ASJ

AF:

0.0372

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0516

Gnomad4 FIN

AF:

0.0490

Gnomad4 NFE

AF:

0.0611

Gnomad4 OTH

AF:

0.0468

Alfa

AF:

0.0524

Hom.:

388

Bravo

AF:

0.0378

TwinsUK

AF:

0.0628

AC:

233

ALSPAC

AF:

0.0649

AC:

250

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.0609

AC:

524

ExAC

AF:

0.0459

AC:

5577

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0622

EpiControl

AF:

0.0614

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Likely 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	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Iodotyrosyl coupling defect

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.19

Sift

Benign

0.22

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.017

B;B

Vest4

0.15

MPC

0.062

ClinPred

0.0051

GERP RS

-7.2

Varity_R

0.10

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00034

dbscSNV1_RF

Benign

0.012

SpliceAI score (max)

0.060

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