rs2132013784

Variant names:

• chr8-132867003-G-T
• rs2132013784
• NM_003235.5:c.3G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003235.5(TG):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TG NM_003235.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 146 codons. Genomic position: 132871509. Lost 0.052 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.3G>T	p.Met1?	start_lost	Exon 1 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.3G>T	p.Met1?	start_lost	Exon 1 of 48	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523901.1	n.3G>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000427871.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441872 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 42938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 38964

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100612

Other (OTH) AF: 0.00 AC: 0 AN: 59560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Iodotyrosyl coupling defect Uncertain:1

Jan 03, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alterante start codon (PVS1_M). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.75	T
PhyloP100		3.1
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.13	B
Vest4		0.79
MutPred		0.90		Gain of catalytic residue at M1 (P = 0.0116);
MVP		0.65
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		-0.22	Neutral
Varity_R		0.86
gMVP		0.63
Mutation Taster		=18/182	disease causing

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: rs2132013784; hg19: chr8-133879248;