chr8-132917672-C-T

Variant names:

• chr8-132917672-C-T
• rs853308
• NM_003235.5:c.4379-1704C>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.4379-1704C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,532 control chromosomes in the GnomAD database, including 15,659 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 (15659 hom., cov: 28)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.448
• Publications: 29 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.527 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.4379-1704C>T		intron	N/A	NP_003226.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.4379-1704C>T		intron	N/A	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.*592-1704C>T		intron	N/A	ENSP00000428628.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62474 AN: 151414 Hom.: 15660 Cov.: 28

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.412 AC: 62474 AN: 151532 Hom.: 15659 Cov.: 28 AF XY: 0.418 AC XY: 30942 AN XY: 74004

African (AFR) AF: 0.114 AC: 4722 AN: 41324

American (AMR) AF: 0.536 AC: 8169 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1802 AN: 5068

South Asian (SAS) AF: 0.498 AC: 2387 AN: 4792

European-Finnish (FIN) AF: 0.614 AC: 6420 AN: 10454

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35770 AN: 67894

Other (OTH) AF: 0.435 AC: 912 AN: 2098

Alfa AF: 0.494 Hom.: 81226

Bravo AF: 0.394

Asia WGS AF: 0.422 AC: 1471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.5
DANN	Benign	0.82
PhyloP100		-0.45
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: rs853308; hg19: chr8-133929917;