rs190979363

Variant names:

• chr8-133116600-T-G
• rs190979363
• NM_003235.5:c.7755-9T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003235.5(TG):​c.7755-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,611,926 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (28 hom.)
• Consequence: TG NM_003235.5 intron
• Scores: Splicing: ADA: 0.003053
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.850
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-133116600-T-G is Benign according to our data. Variant chr8-133116600-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376938.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (685/152346) while in subpopulation NFE AF = 0.00662 (450/68016). AF 95% confidence interval is 0.00611. There are 2 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7755-9T>G		intron_variant	Intron 44 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7755-9T>G		intron_variant	Intron 44 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152230 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00662

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00450 AC: 1132 AN: 251476 AF XY: 0.00447

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00631

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00526 AC: 7679 AN: 1459580 Hom.: 28 Cov.: 30 AF XY: 0.00516 AC XY: 3750 AN XY: 726254

African (AFR) AF: 0.000628 AC: 21 AN: 33440

American (AMR) AF: 0.00121 AC: 54 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86220

European-Finnish (FIN) AF: 0.0127 AC: 677 AN: 53410

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5758

European-Non Finnish (NFE) AF: 0.00590 AC: 6548 AN: 1109922

Other (OTH) AF: 0.00415 AC: 250 AN: 60306

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00468 AC XY: 349 AN XY: 74506

African (AFR) AF: 0.000914 AC: 38 AN: 41588

American (AMR) AF: 0.00144 AC: 22 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00662 AC: 450 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00550 Hom.: 1

Bravo AF: 0.00331

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Iodotyrosyl coupling defect Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.4
DANN	Benign	0.51
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0031
dbscSNV1_RF	Benign	0.12
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: rs190979363; hg19: chr8-134128844;