8-133096302-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003235.5(TG):c.7501T>C(p.Trp2501Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,940 control chromosomes in the GnomAD database, including 228,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2501Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 27591 hom., cov: 32)

Exomes 𝑓: 0.52 ( 200444 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.108

Publications

31 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3603862E-6).

BP6

Variant 8-133096302-T-C is Benign according to our data. Variant chr8-133096302-T-C is described in ClinVar as Benign. ClinVar VariationId is 259001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.7501T>C	p.Trp2501Arg	missense_variant	Exon 43 of 48	ENST00000220616.9	NP_003226.4	P01266-1
SLA	NM_001045556.3 link	c.-319+6251A>G		intron_variant	Intron 1 of 8	ENST00000338087.10	NP_001039021.1	Q13239-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 link	c.7501T>C	p.Trp2501Arg	missense_variant	Exon 43 of 48	1	NM_003235.5	ENSP00000220616.4		P01266-1
SLA	ENST00000338087.10 link	c.-319+6251A>G		intron_variant	Intron 1 of 8	1	NM_001045556.3	ENSP00000337548.5		Q13239-1

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88946

AN:

151970

Hom.:

27559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.788

Gnomad AMI

AF:

0.564

Gnomad AMR

AF:

0.515

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.237

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.534

Gnomad OTH

AF:

0.577

GnomAD2 exomes

AF:

0.496

AC:

124629

AN:

251420

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.795

Gnomad AMR exome

AF:

0.429

Gnomad ASJ exome

AF:

0.599

Gnomad EAS exome

AF:

0.226

Gnomad FIN exome

AF:

0.467

Gnomad NFE exome

AF:

0.534

Gnomad OTH exome

AF:

0.514

GnomAD4 exome

AF:

0.518

AC:

757575

AN:

1461856

Hom.:

200444

Cov.:

AF XY:

0.515

AC XY:

374669

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.799

AC:

26752

AN:

33480

American (AMR)

AF:

0.443

AC:

19817

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

15606

AN:

26136

East Asian (EAS)

AF:

0.230

AC:

9135

AN:

39700

South Asian (SAS)

AF:

0.422

AC:

36360

AN:

86256

European-Finnish (FIN)

AF:

0.462

AC:

24693

AN:

53414

Middle Eastern (MID)

AF:

0.538

AC:

3103

AN:

5768

European-Non Finnish (NFE)

AF:

0.531

AC:

590439

AN:

1111986

Other (OTH)

AF:

0.524

AC:

31670

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21220

42440

63659

84879

106099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16720

33440

50160

66880

83600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.585

AC:

89025

AN:

152084

Hom.:

27591

Cov.:

AF XY:

0.578

AC XY:

42977

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.788

AC:

32718

AN:

41506

American (AMR)

AF:

0.514

AC:

7858

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2068

AN:

3468

East Asian (EAS)

AF:

0.237

AC:

1223

AN:

5152

South Asian (SAS)

AF:

0.416

AC:

1999

AN:

4804

European-Finnish (FIN)

AF:

0.468

AC:

4943

AN:

10568

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.534

AC:

36326

AN:

67996

Other (OTH)

AF:

0.573

AC:

1208

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1760

3521

5281

7042

8802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.542

Hom.:

76640

Bravo

AF:

0.591

TwinsUK

AF:

0.527

AC:

1953

ALSPAC

AF:

0.539

AC:

2078

ESP6500AA

AF:

0.786

AC:

3462

ESP6500EA

AF:

0.527

AC:

4533

ExAC

AF:

0.502

AC:

60983

Asia WGS

AF:

0.341

AC:

1189

AN:

3478

EpiCase

AF:

0.528

EpiControl

AF:

0.530

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Iodotyrosyl coupling defect

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.93

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.051

T;T

MetaRNN

Benign

0.0000014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;.

PhyloP100

0.11

PrimateAI

Benign

0.31

PROVEAN

Benign

0.080

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.50

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0

B;B

Vest4

0.10

MutPred

0.46

Gain of disorder (P = 0.011);.;

MPC

0.12

ClinPred

0.0047

GERP RS

2.0

Varity_R

0.19

gMVP

0.80

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over