rs2261147

chr8-132908166-T-C

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: 0.838

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 258992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132908166-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.3848-20T>C		intron_variant		ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.3848-20T>C		intron_variant		1	NM_003235.5	P1
TG	ENST00000523756.5	c.*61-20T>C		intron_variant, NMD_transcript_variant		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

GnomAD3 exomes AF: 0.577 AC: 144436 AN: 250176 Hom.: 44313 AF XY: 0.584 AC XY: 79013 AN XY: 135352

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 SAS exome AF: 0.577

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

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.580

Gnomad4 FIN exome AF: 0.701

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.562

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

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.693

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.500

Alfa AF: 0.548 Hom.: 4269

Bravo AF: 0.460

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Iodotyrosyl coupling defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs2261147; hg19: chr8-133920411; COSMIC: COSV55069737; COSMIC: COSV55069737;