rs121912648

Positions:

chr8-132882609-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_003235.5(TG):c.886C>T(p.Arg296Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,614,008 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 3 hom. )

Consequence

TG
NM_003235.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.54

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 8-132882609-C-T is Pathogenic according to our data. Variant chr8-132882609-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132882609-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5 linkuse as main transcript	c.886C>T	p.Arg296Ter	stop_gained	7/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.886C>T	p.Arg296Ter	stop_gained	7/48	1	NM_003235.5	P1	P01266-1
TG	ENST00000520769.1 linkuse as main transcript	n.239C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000362

AC:

AN:

251480

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000549

AC:

803

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000528

AC XY:

384

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000629

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000394

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000526

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Iodotyrosyl coupling defect

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2020	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 17, 2014	This patient is a carrier of a heterozygous pathogenic variant in the TG gene associated with thyroid dyshormonogenesis. The TG variant (c.886C>T; p.Arg296*) identified in this patient is a nonsense variant which results in a truncated protein, considered a pathogenic variant and has been reported in other individuals with goitre and hypothyroidism (Van da Graaf et al. 1999, PMID: 10404833; Gutnisky et al. 2004, PMID: 14764776; Rivolta et al. 2005, PMID: 15769978; Caputo et al. 2007, PMID: 17532758; Peteiro-Gonzalez et al. 2010, PMID: 20410234). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 24, 2018	The TG c.886C>T (p.Arg296Ter) variant is a stop-gained variant which has been reported in at least six studies in which it is found in a total of 15 patients with clinical suspicion of thyroid dyshoromonogenesis, including five in a homozygous state and ten in a compound heterozygous state (van de Graaf et al. 1999; Gutnisky et al. 2004; Rivolta et al. 2005; Peteiro-Gonzalez et al. 2010; Citterio et al. 2011; Citterio et al. 2013). In all families, the p.Arg296Ter variant was identified in unaffected individuals in a heterozygous state. Control data are unavailable for this variant, which is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. RT-PCR analysis on patient cDNA showed very little transcript was present from the p.Arg296Ter variant allele (Peteiro-Gonzalez et al. 2010). Based on the collective evidence, the p.Arg296Ter variant is classified as pathogenic for thyroid dyshormonogenesis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23164529, 21128992, 25525159, 20410234, 9588493, 15769978, 26990548, 28359061, 29546359, 29275168, 28176629, 34426522, 33692749, 32765423, 31589614, 33321114, 10404833, 14764776) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg296*) in the TG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TG are known to be pathogenic (PMID: 19837936, 23164529). This variant is present in population databases (rs121912648, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with congenital hypothyroidism and goiter (PMID: 10404833, 14764776, 20410234, 21372558, 23164529). It has also been observed to segregate with disease in related individuals. This variant is also known as R277X. ClinVar contains an entry for this variant (Variation ID: 12695). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -

Congenital hypothyroidism

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Polak associated Lab, IMAGINE Institute

- -

TG-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 15, 2024

Variant summary: TG c.886C>T (p.Arg296X) results in a premature termination codon, predicted to cause nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00036 in 251480 control chromosomes. c.886C>T has been reported in the literature in multiple individuals affected with TG-Related Disorders (example, van de Graaf_1999). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (van de Graaf_1999). The following publication have been ascertained in the context of this evaluation (PMID: 10404833). ClinVar contains an entry for this variant (Variation ID: 12695). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A

Vest4

0.95

GERP RS

5.6

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