Genetic Variant TG:c.68-148G>A (chr8-132867967-G-A) – ACMG Classification: Benign (-20 pts)

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.68-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 698,438 control chromosomes in the GnomAD database, including 161,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41721 hom., cov: 31)

Exomes 𝑓: 0.66 ( 119715 hom. )

Consequence

TG
NM_003235.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.539

Publications

3 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 (BayesDel_noAF=-0.99).

BP6

Variant 8-132867967-G-A is Benign according to our data. Variant chr8-132867967-G-A is described in ClinVar as [Benign]. Clinvar id is 1246076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.68-148G>A		intron_variant	Intron 1 of 47	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.68-148G>A		intron_variant	Intron 1 of 47	1	NM_003235.5	ENSP00000220616.4		P01266-1
TG	ENST00000523901.1 link	n.68-148G>A		intron_variant	Intron 1 of 5	5		ENSP00000427871.1		E5RG33

Frequencies

GnomAD3 genomes

AF:

0.729

AC:

110743

AN:

151950

Hom.:

41652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.934

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.649

Gnomad ASJ

AF:

0.572

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.636

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.695

GnomAD4 exome

AF:

0.657

AC:

359143

AN:

546370

Hom.:

119715

AF XY:

0.649

AC XY:

189821

AN XY:

292460

show subpopulations

African (AFR)

AF:

0.929

AC:

14170

AN:

15252

American (AMR)

AF:

0.660

AC:

21377

AN:

32394

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

10536

AN:

18126

East Asian (EAS)

AF:

0.719

AC:

22879

AN:

31806

South Asian (SAS)

AF:

0.539

AC:

31236

AN:

57980

European-Finnish (FIN)

AF:

0.649

AC:

24495

AN:

37716

Middle Eastern (MID)

AF:

0.638

AC:

1533

AN:

2402

European-Non Finnish (NFE)

AF:

0.664

AC:

213127

AN:

320834

Other (OTH)

AF:

0.663

AC:

19790

AN:

29860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

6292

12583

18875

25166

31458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.729

AC:

110879

AN:

152068

Hom.:

41721

Cov.:

AF XY:

0.721

AC XY:

53586

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.934

AC:

38762

AN:

41498

American (AMR)

AF:

0.649

AC:

9929

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.572

AC:

1987

AN:

3472

East Asian (EAS)

AF:

0.674

AC:

3473

AN:

5156

South Asian (SAS)

AF:

0.541

AC:

2601

AN:

4804

European-Finnish (FIN)

AF:

0.636

AC:

6724

AN:

10576

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45107

AN:

67960

Other (OTH)

AF:

0.700

AC:

1478

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1441

2882

4324

5765

7206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.718

Hom.:

5191

Bravo

AF:

0.742

Asia WGS

AF:

0.625

AC:

2173

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.57

(source)

DANN

Benign

0.13

PhyloP100

-0.54

Mutation Taster

=100/0

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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8-132867967-G-A

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