rs56230101

Variant names:

• chr8-132969515-T-C
• rs56230101
• NM_003235.5:c.5921T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-132969515-T-C
• chr8-132969515-T-G

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.5921T>C​(p.Met1974Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,613,072 control chromosomes in the GnomAD database, including 7,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1974I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (2088 hom., cov: 31)
  • Exomes 𝑓: 0.073 (5126 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.818
• Publications: 13 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 (MetaRNN=0.0054279864).
• BP6: Variant 8-132969515-T-C is Benign according to our data. Variant chr8-132969515-T-C is described in ClinVar as Benign. ClinVar VariationId is 258997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.5921T>C	p.Met1974Thr	missense_variant	Exon 32 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.5921T>C	p.Met1974Thr	missense_variant	Exon 32 of 48	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19610 AN: 151990 Hom.: 2072 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0787

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0789 AC: 19824 AN: 251396 AF XY: 0.0777

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.0443

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0665

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0838

GnomAD4 exome AF: 0.0730 AC: 106676 AN: 1460962 Hom.: 5126 Cov.: 31 AF XY: 0.0726 AC XY: 52772 AN XY: 726820

African (AFR) AF: 0.306 AC: 10211 AN: 33410

American (AMR) AF: 0.0479 AC: 2143 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0816 AC: 2131 AN: 26126

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39692

South Asian (SAS) AF: 0.0781 AC: 6732 AN: 86210

European-Finnish (FIN) AF: 0.0684 AC: 3656 AN: 53416

Middle Eastern (MID) AF: 0.105 AC: 603 AN: 5764

European-Non Finnish (NFE) AF: 0.0687 AC: 76315 AN: 1111280

Other (OTH) AF: 0.0807 AC: 4872 AN: 60346

GnomAD4 genome AF: 0.129 AC: 19661 AN: 152110 Hom.: 2088 Cov.: 31 AF XY: 0.126 AC XY: 9348 AN XY: 74392

African (AFR) AF: 0.295 AC: 12206 AN: 41440

American (AMR) AF: 0.0714 AC: 1092 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 273 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0684 AC: 330 AN: 4822

European-Finnish (FIN) AF: 0.0678 AC: 718 AN: 10596

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4726 AN: 67998

Other (OTH) AF: 0.121 AC: 255 AN: 2112

Alfa AF: 0.0909 Hom.: 2011

Bravo AF: 0.137

TwinsUK AF: 0.0669 AC: 248

ALSPAC AF: 0.0664 AC: 256

ESP6500AA AF: 0.290 AC: 1278

ESP6500EA AF: 0.0736 AC: 633

ExAC AF: 0.0842 AC: 10220

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.0721

EpiControl AF: 0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Iodotyrosyl coupling defect Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.021
DANN	Benign	0.18
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.069	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;.
PhyloP100		-0.82
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.074
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.024
MPC		0.078
ClinPred		0.0030	T
GERP RS		-0.078
Varity_R		0.13
gMVP		0.28
Mutation Taster		=97/3	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: rs56230101; hg19: chr8-133981760; COSMIC: COSV107274921;