rs2687834

Variant names:

• chr8-132909582-G-T
• rs2687834
• NM_003235.5:c.4002+1242G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003235.5(TG):​c.4002+1242G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,932 control chromosomes in the GnomAD database, including 15,547 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 0.41 (15547 hom., cov: 31)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440
• Publications: 6 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.4002+1242G>T		intron_variant	Intron 18 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.4002+1242G>T		intron_variant	Intron 18 of 47	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523756.5	n.*215+1242G>T		intron_variant	Intron 5 of 34	1		ENSP00000428628.1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62078 AN: 151814 Hom.: 15548 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.440

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

GnomAD4 genome AF: 0.409 AC: 62072 AN: 151932 Hom.: 15547 Cov.: 31 AF XY: 0.415 AC XY: 30780 AN XY: 74230

African (AFR) AF: 0.107 AC: 4429 AN: 41466

American (AMR) AF: 0.535 AC: 8157 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1695 AN: 3468

East Asian (EAS) AF: 0.356 AC: 1833 AN: 5144

South Asian (SAS) AF: 0.498 AC: 2398 AN: 4816

European-Finnish (FIN) AF: 0.610 AC: 6429 AN: 10540

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35566 AN: 67928

Other (OTH) AF: 0.433 AC: 913 AN: 2110

Alfa AF: 0.466 Hom.: 3086

Bravo AF: 0.390

Asia WGS AF: 0.417 AC: 1456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.40
PhyloP100		0.044
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2687834; hg19: chr8-133921827;