8-132908166-T-C

Variant names:

• chr8-132908166-T-C
• rs2261147
• NM_003235.5:c.3848-20T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(TG):​c.3848-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 1,611,638 control chromosomes in the GnomAD database, including 291,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (21033 hom., cov: 32)
  • Exomes 𝑓: 0.60 (270496 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.838
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 8-132908166-T-C is Benign according to our data. Variant chr8-132908166-T-C is described in ClinVar as Benign. ClinVar VariationId is 258992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 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.3848-20T>C		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.3848-20T>C		intron	N/A	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.*61-20T>C		intron	N/A	ENSP00000428628.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73043 AN: 151812 Hom.: 21030 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.577 AC: 144436 AN: 250176 AF XY: 0.584

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.676

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.364

Gnomad FIN exome AF: 0.699

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.601 AC: 877469 AN: 1459708 Hom.: 270496 Cov.: 45 AF XY: 0.601 AC XY: 436790 AN XY: 726258

African (AFR) AF: 0.136 AC: 4556 AN: 33466

American (AMR) AF: 0.663 AC: 29652 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 14412 AN: 26126

East Asian (EAS) AF: 0.363 AC: 14414 AN: 39666

South Asian (SAS) AF: 0.580 AC: 49977 AN: 86204

European-Finnish (FIN) AF: 0.701 AC: 36926 AN: 52662

Middle Eastern (MID) AF: 0.550 AC: 3171 AN: 5766

European-Non Finnish (NFE) AF: 0.622 AC: 690468 AN: 1110782

Other (OTH) AF: 0.562 AC: 33893 AN: 60344

GnomAD4 genome AF: 0.481 AC: 73051 AN: 151930 Hom.: 21033 Cov.: 32 AF XY: 0.486 AC XY: 36087 AN XY: 74250

African (AFR) AF: 0.152 AC: 6313 AN: 41518

American (AMR) AF: 0.586 AC: 8941 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1896 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1834 AN: 5138

South Asian (SAS) AF: 0.549 AC: 2639 AN: 4808

European-Finnish (FIN) AF: 0.693 AC: 7318 AN: 10558

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42270 AN: 67874

Other (OTH) AF: 0.500 AC: 1052 AN: 2104

Alfa AF: 0.537 Hom.: 4280

Bravo AF: 0.460

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Iodotyrosyl coupling defect Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.84
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: rs2261147; hg19: chr8-133920411; COSMIC: COSV55069737; COSMIC: COSV55069737;