rs2979040

Variant names:

• chr8-133112785-G-A
• rs2979040
• NM_003235.5:c.7573-637G>A

Variant summary

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

The NM_003235.5(TG):​c.7573-637G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,932 control chromosomes in the GnomAD database, including 4,212 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 0.22 (4212 hom., cov: 31)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.358
• Publications: 3 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7573-637G>A		intron_variant	Intron 43 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7573-637G>A		intron_variant	Intron 43 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33477 AN: 151814 Hom.: 4211 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.221 AC: 33501 AN: 151932 Hom.: 4212 Cov.: 31 AF XY: 0.226 AC XY: 16778 AN XY: 74236

African (AFR) AF: 0.118 AC: 4900 AN: 41458

American (AMR) AF: 0.186 AC: 2836 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 809 AN: 3466

East Asian (EAS) AF: 0.231 AC: 1188 AN: 5148

South Asian (SAS) AF: 0.312 AC: 1504 AN: 4814

European-Finnish (FIN) AF: 0.333 AC: 3510 AN: 10528

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17912 AN: 67924

Other (OTH) AF: 0.216 AC: 456 AN: 2108

Alfa AF: 0.248 Hom.: 8700

Bravo AF: 0.201

Asia WGS AF: 0.240 AC: 840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.1
DANN	Benign	0.37
PhyloP100		0.36
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: rs2979040; hg19: chr8-134125029;