rs180202

Variant names:

• chr8-132867967-G-A
• rs180202
• NM_003235.5:c.68-148G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.68-148G>A		intron	N/A	NP_003226.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.68-148G>A		intron	N/A	ENSP00000220616.4
	TG	ENST00000523901.1	TSL:5	n.68-148G>A		intron	N/A	ENSP00000427871.1

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

African (AFR) AF: 0.929 AC: 14170 AN: 15252

American (AMR) AF: 0.660 AC: 21377 AN: 32394

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 10536 AN: 18126

East Asian (EAS) AF: 0.719 AC: 22879 AN: 31806

South Asian (SAS) AF: 0.539 AC: 31236 AN: 57980

European-Finnish (FIN) AF: 0.649 AC: 24495 AN: 37716

Middle Eastern (MID) AF: 0.638 AC: 1533 AN: 2402

European-Non Finnish (NFE) AF: 0.664 AC: 213127 AN: 320834

Other (OTH) AF: 0.663 AC: 19790 AN: 29860

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

African (AFR) AF: 0.934 AC: 38762 AN: 41498

American (AMR) AF: 0.649 AC: 9929 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1987 AN: 3472

East Asian (EAS) AF: 0.674 AC: 3473 AN: 5156

South Asian (SAS) AF: 0.541 AC: 2601 AN: 4804

European-Finnish (FIN) AF: 0.636 AC: 6724 AN: 10576

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45107 AN: 67960

Other (OTH) AF: 0.700 AC: 1478 AN: 2110

Alfa AF: 0.718 Hom.: 5191

Bravo AF: 0.742

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.57
DANN	Benign	0.13
PhyloP100		-0.54
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: rs180202; hg19: chr8-133880212; COSMIC: COSV55087812;