rs2068128

Variant names:

• chr8-132905343-G-A
• rs2068128
• NM_003235.5:c.3635-1345G>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.3635-1345G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 151,994 control chromosomes in the GnomAD database, including 20,463 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 0.49 (20463 hom., cov: 32)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.958
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.3635-1345G>A		intron_variant	Intron 16 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.3635-1345G>A		intron_variant	Intron 16 of 47	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523756.5	n.289-1345G>A		intron_variant	Intron 3 of 34	1		ENSP00000428628.1
TG	ENST00000518505.1	c.464-1345G>A		intron_variant	Intron 5 of 5	4		ENSP00000429605.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74206 AN: 151876 Hom.: 20462 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.504

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

GnomAD4 genome AF: 0.488 AC: 74220 AN: 151994 Hom.: 20463 Cov.: 32 AF XY: 0.491 AC XY: 36490 AN XY: 74282

African (AFR) AF: 0.221 AC: 9148 AN: 41432

American (AMR) AF: 0.570 AC: 8703 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1780 AN: 3464

East Asian (EAS) AF: 0.342 AC: 1770 AN: 5170

South Asian (SAS) AF: 0.544 AC: 2612 AN: 4804

European-Finnish (FIN) AF: 0.646 AC: 6836 AN: 10586

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.612 AC: 41569 AN: 67966

Other (OTH) AF: 0.497 AC: 1045 AN: 2104

Alfa AF: 0.564 Hom.: 9833

Bravo AF: 0.470

Asia WGS AF: 0.427 AC: 1487 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.22
DANN	Benign	0.56
PhyloP100		-0.96
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: rs2068128; hg19: chr8-133917588;