rs190979363

Positions:

• chr8-133116600-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003235.5(TG):​c.7755-9T>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003053
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.850

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 -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 id is 376938.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr8-133116600-T-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TG	NM_003235.5	c.7755-9T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7755-9T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003235.5	ENSP00000220616	P1

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

GnomAD3 exomes AF: 0.00450 AC: 1132 AN: 251476 Hom.: 3 AF XY: 0.00447 AC XY: 607 AN XY: 135912

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00415

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

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.00662

Gnomad4 OTH AF: 0.00284

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

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Iodotyrosyl coupling defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs190979363; hg19: chr8-134128844;