8-133128302-C-T

Variant names:

• chr8-133128302-C-T
• rs17705719
• NM_003235.5:c.7863-3510C>T

Variant summary

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

The NM_003235.5(TG):​c.7863-3510C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 146,258 control chromosomes in the GnomAD database, including 3,858 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 0.21 (3858 hom., cov: 28)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 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.7863-3510C>T		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.7863-3510C>T		intron	N/A	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.*4076-3510C>T		intron	N/A	ENSP00000428628.1
	TG	ENST00000519178.5	TSL:2	c.3228-3510C>T		intron	N/A	ENSP00000430523.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 31422 AN: 146148 Hom.: 3859 Cov.: 28

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.00316

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.215 AC: 31427 AN: 146258 Hom.: 3858 Cov.: 28 AF XY: 0.209 AC XY: 14780 AN XY: 70850

African (AFR) AF: 0.153 AC: 6041 AN: 39526

American (AMR) AF: 0.280 AC: 4047 AN: 14476

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1238 AN: 3432

East Asian (EAS) AF: 0.00317 AC: 15 AN: 4738

South Asian (SAS) AF: 0.127 AC: 565 AN: 4444

European-Finnish (FIN) AF: 0.127 AC: 1188 AN: 9382

Middle Eastern (MID) AF: 0.272 AC: 79 AN: 290

European-Non Finnish (NFE) AF: 0.262 AC: 17562 AN: 67050

Other (OTH) AF: 0.236 AC: 478 AN: 2024

Alfa AF: 0.246 Hom.: 7733

Bravo AF: 0.218

Asia WGS AF: 0.0690 AC: 237 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.19
DANN	Benign	0.76
PhyloP100		-2.2
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: rs17705719; hg19: chr8-134140546;