rs114436500

Positions:

chr8-132868191-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003235.5(TG):c.144C>T(p.Tyr48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,124 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 15 hom. )

Consequence

TG
NM_003235.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -2.12

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 8-132868191-C-T is Benign according to our data. Variant chr8-132868191-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436995.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr8-132868191-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00376 (5502/1461876) while in subpopulation MID AF= 0.0194 (112/5766). AF 95% confidence interval is 0.0165. There are 15 homozygotes in gnomad4_exome. There are 2791 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TG	NM_003235.5 linkuse as main transcript	c.144C>T	p.Tyr48=	synonymous_variant	2/48	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.144C>T	p.Tyr48=	synonymous_variant	2/48	1	NM_003235.5	ENSP00000220616	P1	P01266-1
TG	ENST00000523901.1 linkuse as main transcript	c.144C>T	p.Tyr48=	synonymous_variant, NMD_transcript_variant	2/6	5		ENSP00000427871

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

542

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00629

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00367

AC:

923

AN:

251430

Hom.:

AF XY:

0.00372

AC XY:

506

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00432

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.00376

AC:

5502

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2791

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00434

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00368

Gnomad4 OTH exome

AF:

0.00583

GnomAD4 genome

AF:

0.00356

AC:

542

AN:

152248

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00628

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00458

Hom.:

Bravo

AF:

0.00386

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TG: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

TG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

3.6

DANN

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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