rs2294025

Variant names:

• chr8-133133268-G-A
• rs2294025
• NM_003235.5:c.7998-202G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003235.5(TG):​c.7998-202G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 646,410 control chromosomes in the GnomAD database, including 68,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (18012 hom., cov: 32)
  • Exomes 𝑓: 0.44 (50178 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33
• Publications: 19 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-133133268-G-A is Benign according to our data. Variant chr8-133133268-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279842.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7998-202G>A		intron_variant	Intron 46 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7998-202G>A		intron_variant	Intron 46 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72661 AN: 151834 Hom.: 18003 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.438 AC: 216331 AN: 494458 Hom.: 50178 AF XY: 0.432 AC XY: 113906 AN XY: 263466

African (AFR) AF: 0.549 AC: 7868 AN: 14326

American (AMR) AF: 0.406 AC: 12062 AN: 29708

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 8737 AN: 15718

East Asian (EAS) AF: 0.122 AC: 3806 AN: 31156

South Asian (SAS) AF: 0.322 AC: 16724 AN: 52006

European-Finnish (FIN) AF: 0.399 AC: 12717 AN: 31840

Middle Eastern (MID) AF: 0.507 AC: 1320 AN: 2606

European-Non Finnish (NFE) AF: 0.484 AC: 140066 AN: 289260

Other (OTH) AF: 0.468 AC: 13031 AN: 27838

GnomAD4 genome AF: 0.478 AC: 72697 AN: 151952 Hom.: 18012 Cov.: 32 AF XY: 0.467 AC XY: 34701 AN XY: 74286

African (AFR) AF: 0.554 AC: 22968 AN: 41432

American (AMR) AF: 0.449 AC: 6858 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1965 AN: 3470

East Asian (EAS) AF: 0.164 AC: 846 AN: 5164

South Asian (SAS) AF: 0.310 AC: 1492 AN: 4818

European-Finnish (FIN) AF: 0.378 AC: 3990 AN: 10548

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33044 AN: 67932

Other (OTH) AF: 0.496 AC: 1046 AN: 2108

Alfa AF: 0.476 Hom.: 36275

Bravo AF: 0.488

Asia WGS AF: 0.234 AC: 815 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.72
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: rs2294025; hg19: chr8-134145512;