rs142698837

Positions:

chr8-132869781-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP3_ModeratePP5BS2_Supporting

The NM_003235.5(TG):c.229G>A(p.Gly77Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:6

Conservation

PhyloP100: 8.61

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

PP5

Variant 8-132869781-G-A is Pathogenic according to our data. Variant chr8-132869781-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436996.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=6, Pathogenic=2}. Variant chr8-132869781-G-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TG	NM_003235.5 linkuse as main transcript	c.229G>A	p.Gly77Ser	missense_variant	3/48	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.229G>A	p.Gly77Ser	missense_variant	3/48	1	NM_003235.5	ENSP00000220616	P1	P01266-1
TG	ENST00000523901.1 linkuse as main transcript	c.*80G>A		3_prime_UTR_variant, NMD_transcript_variant	3/6	5		ENSP00000427871

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000756

AC:

190

AN:

251242

Hom.:

AF XY:

0.000780

AC XY:

106

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000972

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00123

AC:

1800

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

843

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152302

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000936

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.000791

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 77 of the TG protein (p.Gly77Ser). This variant is present in population databases (rs142698837, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital hypothyroidism (PMID: 10403171, 29590070, 34248839). ClinVar contains an entry for this variant (Variation ID: 436996). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 29590070). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23933148, 34426522, 29590070, 33726816, 34484748, 34248839, 10403171, 34780050) -

Iodotyrosyl coupling defect

Pathogenic:2Uncertain:2

Pathogenic, criteria provided, single submitter	in vitro;research	Center for Precision Medicine, Vanderbilt University Medical Center	Mar 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 22, 2022	The TG c.229G>A variant is classified as Likely Pathogenic (PM1, PM3_Strong, PP3) The TG c.229G>A variant is a single nucleotide change in exon 3/48 of the TG gene, which is predicted to change the amino acid glycine at position 77 in the protein to serine. This variant is located in the conserved thyroglobulin-1 domain (PM1). This variant has been detected in trans with a pathogenic variant as well as homozygous in patients with congenital hypothyroidism (PMID:10403171, 34484748) (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs142698837), in population databases (gnomAD 104/152184, 0 homozygotes) and as disease causing in the HGMD database (CM994510). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 436996). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2019	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2018	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly77Ser variant in TG has been reported in the homozygous state in 3 individuals with co ngenital hypothyroidism (van de Graaf 1999) and has been reported in ClinVar (Va riation ID: 436996). This variant has been identified in 0.13% (167/126550) of E uropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs142698837). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. In vitro functional studies suggest that the p.Gly77Ser variant leads to th e use of an alternative splice site (Bastarache 2018); however, these types of a ssays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this varia nt is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PS3_Supporting, PM3_Su pporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -

TG-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 15, 2023

Variant summary: TG c.229G>A (p.Gly77Ser) results in a non-conservative amino acid change located in the Thyroglobulin type-1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing (Bastarache_2018). The variant allele was found at a frequency of 0.00076 in 251242 control chromosomes with no homozygous occurrences in the database (gnomad). c.229G>A has been reported in the literature in multiple individuals affected with TG-Related Disorders, including consanguineous patients who have the variant in the homozygous state (vandeGraaf_TG_Bioch_1999, Acar_2022) and patients who have the variant in the compound heterozygous state with other missense or nonsense variants, with at least one confirmed as being in-trans (Machiavelli_2009, Oliver-Petit_2021). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Two submitters classified the variants as likely pathogenic/pathogenic while five classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Iodotyrosyl coupling defect;C1842444:Autoimmune thyroid disease, susceptibility to, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.82

Sift

Uncertain

0.013

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.93

MPC

0.41

ClinPred

1.0

GERP RS

5.4

Varity_R

0.40

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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