8-132948746-C-T

Variant names:

• chr8-132948746-C-T
• rs2246624
• NM_003235.5:c.5234-30C>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.5234-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,611,312 control chromosomes in the GnomAD database, including 503,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48190 hom., cov: 31)
  • Exomes 𝑓: 0.79 (455333 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.60
• Publications: 10 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=-0.97).
• BP6: Variant 8-132948746-C-T is Benign according to our data. Variant chr8-132948746-C-T is described in CliVar as Benign. Clinvar id is 1246261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132948746-C-T is described in CliVar as Benign. Clinvar id is 1246261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132948746-C-T is described in CliVar as Benign. Clinvar id is 1246261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.5234-30C>T		intron_variant	Intron 26 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.5234-30C>T		intron_variant	Intron 26 of 47	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523756.5	n.*1447-30C>T		intron_variant	Intron 13 of 34	1		ENSP00000428628.1
TG	ENST00000519178.5	c.599-30C>T		intron_variant	Intron 5 of 26	2		ENSP00000430523.1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120903 AN: 151968 Hom.: 48152 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.794

GnomAD2 exomes AF: 0.808 AC: 203189 AN: 251320 AF XY: 0.807

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.785

Gnomad OTH exome AF: 0.796

GnomAD4 exome AF: 0.789 AC: 1151730 AN: 1459226 Hom.: 455333 Cov.: 38 AF XY: 0.790 AC XY: 573633 AN XY: 726010

African (AFR) AF: 0.797 AC: 26633 AN: 33408

American (AMR) AF: 0.886 AC: 39640 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19529 AN: 26130

East Asian (EAS) AF: 0.805 AC: 31940 AN: 39696

South Asian (SAS) AF: 0.841 AC: 72476 AN: 86164

European-Finnish (FIN) AF: 0.797 AC: 42487 AN: 53290

Middle Eastern (MID) AF: 0.806 AC: 3673 AN: 4556

European-Non Finnish (NFE) AF: 0.781 AC: 868093 AN: 1111040

Other (OTH) AF: 0.785 AC: 47259 AN: 60218

GnomAD4 genome AF: 0.796 AC: 120988 AN: 152086 Hom.: 48190 Cov.: 31 AF XY: 0.797 AC XY: 59228 AN XY: 74322

African (AFR) AF: 0.798 AC: 33116 AN: 41478

American (AMR) AF: 0.850 AC: 13005 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2576 AN: 3470

East Asian (EAS) AF: 0.801 AC: 4105 AN: 5124

South Asian (SAS) AF: 0.831 AC: 4007 AN: 4822

European-Finnish (FIN) AF: 0.797 AC: 8449 AN: 10596

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53113 AN: 67990

Other (OTH) AF: 0.784 AC: 1649 AN: 2104

Alfa AF: 0.775 Hom.: 15619

Bravo AF: 0.800

Asia WGS AF: 0.780 AC: 2715 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	-0.97
CADD	Benign	0.0080
DANN	Benign	0.43
PhyloP100		-2.6
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: rs2246624; hg19: chr8-133960991;