8-132868089-T-C

Variant names:

• chr8-132868089-T-C
• rs180203
• NM_003235.5:c.68-26T>C

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.68-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,610,584 control chromosomes in the GnomAD database, including 791,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75347 hom., cov: 31)
  • Exomes 𝑓: 0.99 (716457 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169
• Publications: 7 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=-0.9).
• BP6: Variant 8-132868089-T-C is Benign according to our data. Variant chr8-132868089-T-C is described in ClinVar as [Benign]. Clinvar id is 1271560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.68-26T>C		intron_variant	Intron 1 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.68-26T>C		intron_variant	Intron 1 of 47	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523901.1	n.68-26T>C		intron_variant	Intron 1 of 5	5		ENSP00000427871.1

Frequencies

GnomAD3 genomes AF: 0.995 AC: 151371 AN: 152176 Hom.: 75288 Cov.: 31

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.995 AC: 249825 AN: 251068 AF XY: 0.995

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.991

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.991 AC: 1445524 AN: 1458290 Hom.: 716457 Cov.: 30 AF XY: 0.992 AC XY: 719696 AN XY: 725728

African (AFR) AF: 0.999 AC: 33355 AN: 33398

American (AMR) AF: 0.996 AC: 44549 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26095 AN: 26118

East Asian (EAS) AF: 1.00 AC: 39676 AN: 39676

South Asian (SAS) AF: 1.00 AC: 86149 AN: 86188

European-Finnish (FIN) AF: 0.997 AC: 53223 AN: 53398

Middle Eastern (MID) AF: 0.998 AC: 5749 AN: 5760

European-Non Finnish (NFE) AF: 0.989 AC: 1096928 AN: 1108762

Other (OTH) AF: 0.992 AC: 59800 AN: 60268

GnomAD4 genome AF: 0.995 AC: 151489 AN: 152294 Hom.: 75347 Cov.: 31 AF XY: 0.995 AC XY: 74101 AN XY: 74472

African (AFR) AF: 0.998 AC: 41492 AN: 41558

American (AMR) AF: 0.995 AC: 15229 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3466 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 1.00 AC: 4815 AN: 4816

European-Finnish (FIN) AF: 0.998 AC: 10590 AN: 10616

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 0.991 AC: 67419 AN: 68036

Other (OTH) AF: 0.994 AC: 2099 AN: 2112

Alfa AF: 0.994 Hom.: 13386

Bravo AF: 0.994

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Iodotyrosyl coupling defect Benign:1

Sep 10, 2021

Genome-Nilou Lab

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	-0.90
CADD	Benign	7.2
DANN	Benign	0.58
PhyloP100		-0.17
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: rs180203; hg19: chr8-133880334;