rs116062097

chr8-132886939-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003235.5(TG):c.1567T>C(p.Ser523Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,156 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060213506).
• BP6: Variant 8-132886939-T-C is Benign according to our data. Variant chr8-132886939-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 361915.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00186 (2720/1461880) while in subpopulation MID AF= 0.00867 (50/5768). AF 95% confidence interval is 0.00675. There are 6 homozygotes in gnomad4_exome. There are 1358 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.1567T>C	p.Ser523Pro	missense_variant	9/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.1567T>C	p.Ser523Pro	missense_variant	9/48	1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00160 AC: 403 AN: 251162 Hom.: 1 AF XY: 0.00169 AC XY: 230 AN XY: 135808

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1461880 Hom.: 6 Cov.: 32 AF XY: 0.00187 AC XY: 1358 AN XY: 727240

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74454

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00257 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2023	Variant summary: TG c.1567T>C (p.Ser523Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251162 control chromosomes in the gnomAD database, including 1 homozygote. c.1567T>C has been reported in the literature in individuals affected with TG-Related Disorders, without strong evidence for causality (e.g. Barquero_2022). These report(s) do not provide unequivocal conclusions about association of the variant with TG-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36012511, 31287502). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=2) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TG: BP4 -

Iodotyrosyl coupling defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

TG-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.9
Dann	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Benign	0.25	T
Sift4G	Benign	0.067	T
Polyphen		0.049	B
Vest4		0.15
MVP		0.72
MPC		0.094
ClinPred		0.0086	T
GERP RS		2.5
Varity_R		0.15
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs116062097; hg19: chr8-133899184;