rs10505604

Variant names:

• chr8-133015343-A-G
• rs10505604
• NM_003235.5:c.6562+1579A>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.6562+1579A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,174 control chromosomes in the GnomAD database, including 4,440 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 0.24 (4440 hom., cov: 33)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 4 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

LOC105375768 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.6562+1579A>G		intron_variant	Intron 37 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.6562+1579A>G		intron_variant	Intron 37 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36410 AN: 152056 Hom.: 4440 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.246

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

GnomAD4 genome AF: 0.239 AC: 36409 AN: 152174 Hom.: 4440 Cov.: 33 AF XY: 0.239 AC XY: 17794 AN XY: 74404

African (AFR) AF: 0.223 AC: 9275 AN: 41514

American (AMR) AF: 0.176 AC: 2700 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3468

East Asian (EAS) AF: 0.190 AC: 985 AN: 5182

South Asian (SAS) AF: 0.209 AC: 1007 AN: 4824

European-Finnish (FIN) AF: 0.293 AC: 3101 AN: 10580

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17403 AN: 67994

Other (OTH) AF: 0.243 AC: 513 AN: 2110

Alfa AF: 0.245 Hom.: 3600

Bravo AF: 0.233

Asia WGS AF: 0.208 AC: 727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.63
DANN	Benign	0.40
PhyloP100		-1.3
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: rs10505604; hg19: chr8-134027588;