chr8-132963038-G-A

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.5512G>A(p.Asp1838Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,613,286 control chromosomes in the GnomAD database, including 210,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1838D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 14939 hom., cov: 32)

Exomes 𝑓: 0.51 ( 195871 hom. )

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.551

Publications

38 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 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 3
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thyroid cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TG 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=1.5006859E-5).

BP6

Variant 8-132963038-G-A is Benign according to our data. Variant chr8-132963038-G-A is described in CliVar as Benign. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132963038-G-A is described in CliVar as Benign. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132963038-G-A is described in CliVar as Benign. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132963038-G-A is described in CliVar as Benign. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.5512G>A	p.Asp1838Asn	missense_variant	Exon 29 of 48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 link	c.5512G>A	p.Asp1838Asn	missense_variant	Exon 29 of 48	1	NM_003235.5	ENSP00000220616.4		P01266-1

Frequencies

GnomAD3 genomes

AF:

0.402

AC:

60999

AN:

151890

Hom.:

14938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.480

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.349

Gnomad SAS

AF:

0.484

Gnomad FIN

AF:

0.583

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.516

Gnomad OTH

AF:

0.429

GnomAD2 exomes

AF:

0.495

AC:

124497

AN:

251260

AF XY:

0.499

show subpopulations

Gnomad AFR exome

AF:

0.0938

Gnomad AMR exome

AF:

0.632

Gnomad ASJ exome

AF:

0.488

Gnomad EAS exome

AF:

0.354

Gnomad FIN exome

AF:

0.576

Gnomad NFE exome

AF:

0.516

Gnomad OTH exome

AF:

0.508

GnomAD4 exome

AF:

0.511

AC:

747173

AN:

1461278

Hom.:

195871

Cov.:

AF XY:

0.511

AC XY:

371710

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.0898

AC:

3007

AN:

33470

American (AMR)

AF:

0.617

AC:

27586

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

12780

AN:

26124

East Asian (EAS)

AF:

0.365

AC:

14484

AN:

39694

South Asian (SAS)

AF:

0.507

AC:

43730

AN:

86240

European-Finnish (FIN)

AF:

0.577

AC:

30827

AN:

53406

Middle Eastern (MID)

AF:

0.446

AC:

2572

AN:

5764

European-Non Finnish (NFE)

AF:

0.525

AC:

583201

AN:

1111492

Other (OTH)

AF:

0.480

AC:

28986

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

20503

41006

61509

82012

102515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16624

33248

49872

66496

83120

<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:

0.401

AC:

60995

AN:

152008

Hom.:

14939

Cov.:

AF XY:

0.406

AC XY:

30180

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.108

AC:

4486

AN:

41508

American (AMR)

AF:

0.525

AC:

8001

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1674

AN:

3472

East Asian (EAS)

AF:

0.349

AC:

1800

AN:

5162

South Asian (SAS)

AF:

0.485

AC:

2332

AN:

4812

European-Finnish (FIN)

AF:

0.583

AC:

6157

AN:

10556

Middle Eastern (MID)

AF:

0.452

AC:

132

AN:

292

European-Non Finnish (NFE)

AF:

0.516

AC:

35085

AN:

67936

Other (OTH)

AF:

0.422

AC:

890

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1638

3277

4915

6554

8192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.475

Hom.:

67762

Bravo

AF:

0.385

TwinsUK

AF:

0.535

AC:

1984

ALSPAC

AF:

0.538

AC:

2073

ESP6500AA

AF:

0.120

AC:

530

ESP6500EA

AF:

0.511

AC:

4398

ExAC

AF:

0.484

AC:

58829

Asia WGS

AF:

0.413

AC:

1438

AN:

3478

EpiCase

AF:

0.510

EpiControl

AF:

0.501

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2019

GeneDx

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.2

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.048

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.47

MetaRNN

Benign

0.000015

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.0

PhyloP100

0.55

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.84

REVEL

Benign

0.089

Sift

Benign

0.050

Sift4G

Benign

0.35

Polyphen

0.0010

Vest4

0.026

MPC

0.068

ClinPred

0.011

GERP RS

1.7

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.067

gMVP

0.18

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