rs180202

Positions:

• chr8-132867967-G-A
• chr8-132867967-G-T

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.68-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 698,438 control chromosomes in the GnomAD database, including 161,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41721 hom., cov: 31)
  • Exomes 𝑓: 0.66 (119715 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.539

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=-0.99).
• BP6: Variant 8-132867967-G-A is Benign according to our data. Variant chr8-132867967-G-A is described in ClinVar as [Benign]. Clinvar id is 1246076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TG	NM_003235.5	c.68-148G>A		intron_variant		ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.68-148G>A		intron_variant		1	NM_003235.5	ENSP00000220616	P1
TG	ENST00000523901.1	c.68-148G>A		intron_variant, NMD_transcript_variant		5		ENSP00000427871

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110743 AN: 151950 Hom.: 41652 Cov.: 31

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.695

GnomAD4 exome AF: 0.657 AC: 359143 AN: 546370 Hom.: 119715 AF XY: 0.649 AC XY: 189821 AN XY: 292460

Gnomad4 AFR exome AF: 0.929

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.581

Gnomad4 EAS exome AF: 0.719

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.649

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.663

GnomAD4 genome AF: 0.729 AC: 110879 AN: 152068 Hom.: 41721 Cov.: 31 AF XY: 0.721 AC XY: 53586 AN XY: 74322

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.674

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.700

Alfa AF: 0.709 Hom.: 4854

Bravo AF: 0.742

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.57
DANN	Benign	0.13

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: rs180202; hg19: chr8-133880212; COSMIC: COSV55087812;