8-133096209-C-T

Position:

chr8-133096209-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003235.5(TG):c.7408C>T(p.Leu2470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,613,656 control chromosomes in the GnomAD database, including 171,919 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12736 hom., cov: 34)

Exomes 𝑓: 0.46 ( 159183 hom. )

Consequence

TG
NM_003235.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.32

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:

SLA (HGNC:10902): (Src like adaptor) Predicted to enable signaling receptor binding activity. Predicted to be involved in cell differentiation; innate immune response; and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in dendritic spine and focal adhesion. Predicted to be extrinsic component of cytoplasmic side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 8-133096209-C-T is Benign according to our data. Variant chr8-133096209-C-T is described in ClinVar as [Benign]. Clinvar id is 259000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133096209-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5 linkuse as main transcript	c.7408C>T	p.Leu2470=	synonymous_variant	43/48	ENST00000220616.9
SLA	NM_001045556.3 linkuse as main transcript	c.-319+6344G>A		intron_variant		ENST00000338087.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9 linkuse as main transcript	c.7408C>T	p.Leu2470=	synonymous_variant	43/48	1	NM_003235.5	P1	P01266-1
SLA	ENST00000338087.10 linkuse as main transcript	c.-319+6344G>A		intron_variant		1	NM_001045556.3	P1	Q13239-1

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58699

AN:

152056

Hom.:

12741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.448

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.475

Gnomad OTH

AF:

0.399

GnomAD3 exomes

AF:

0.433

AC:

108791

AN:

251364

Hom.:

24761

AF XY:

0.444

AC XY:

60265

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.469

Gnomad EAS exome

AF:

0.395

Gnomad SAS exome

AF:

0.455

Gnomad FIN exome

AF:

0.576

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.447

GnomAD4 exome

AF:

0.462

AC:

675118

AN:

1461482

Hom.:

159183

Cov.:

AF XY:

0.463

AC XY:

336816

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.190

Gnomad4 AMR exome

AF:

0.300

Gnomad4 ASJ exome

AF:

0.470

Gnomad4 EAS exome

AF:

0.361

Gnomad4 SAS exome

AF:

0.457

Gnomad4 FIN exome

AF:

0.571

Gnomad4 NFE exome

AF:

0.476

Gnomad4 OTH exome

AF:

0.450

GnomAD4 genome

AF:

0.386

AC:

58707

AN:

152174

Hom.:

12736

Cov.:

AF XY:

0.389

AC XY:

28953

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.323

Gnomad4 ASJ

AF:

0.448

Gnomad4 EAS

AF:

0.400

Gnomad4 SAS

AF:

0.456

Gnomad4 FIN

AF:

0.575

Gnomad4 NFE

AF:

0.475

Gnomad4 OTH

AF:

0.395

Alfa

AF:

0.425

Hom.:

9337

Bravo

AF:

0.359

Asia WGS

AF:

0.353

AC:

1230

AN:

3478

EpiCase

AF:

0.469

EpiControl

AF:

0.467

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Iodotyrosyl coupling defect

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.8

DANN

Benign

0.75

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