chr8-133110452-A-G

Variant names:

• chr8-133110452-A-G
• rs2979033
• NM_003235.5:c.7573-2970A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003235.5(TG):​c.7573-2970A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 152,228 control chromosomes in the GnomAD database, including 44,840 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44840 hom., cov: 33)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.299
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.7573-2970A>G		intron	N/A	NP_003226.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.7573-2970A>G		intron	N/A	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.*3786-2970A>G		intron	N/A	ENSP00000428628.1
	TG	ENST00000519178.5	TSL:2	c.2938-2970A>G		intron	N/A	ENSP00000430523.1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115309 AN: 152110 Hom.: 44792 Cov.: 33

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.768

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.752

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.758 AC: 115401 AN: 152228 Hom.: 44840 Cov.: 33 AF XY: 0.750 AC XY: 55799 AN XY: 74410

African (AFR) AF: 0.908 AC: 37718 AN: 41556

American (AMR) AF: 0.648 AC: 9914 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2741 AN: 3472

East Asian (EAS) AF: 0.396 AC: 2047 AN: 5172

South Asian (SAS) AF: 0.613 AC: 2960 AN: 4826

European-Finnish (FIN) AF: 0.702 AC: 7429 AN: 10582

Middle Eastern (MID) AF: 0.767 AC: 224 AN: 292

European-Non Finnish (NFE) AF: 0.737 AC: 50158 AN: 68016

Other (OTH) AF: 0.745 AC: 1574 AN: 2112

Alfa AF: 0.768 Hom.: 6492

Bravo AF: 0.757

Asia WGS AF: 0.493 AC: 1719 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.27
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2979033; hg19: chr8-134122696;