rs853326

chr8-132897729-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(TG):c.3082A>G(p.Met1028Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,880 control chromosomes in the GnomAD database, including 242,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28447 hom., cov: 33)
  • Exomes 𝑓: 0.54 (213884 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.416

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1309193E-6).
• BP6: Variant 8-132897729-A-G is Benign according to our data. Variant chr8-132897729-A-G is described in ClinVar as [Benign]. Clinvar id is 12698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132897729-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.3082A>G	p.Met1028Val	missense_variant	12/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.3082A>G	p.Met1028Val	missense_variant	12/48	1	NM_003235.5	P1
TG	ENST00000523756.5	c.43A>G	p.Met15Val	missense_variant, NMD_transcript_variant	1/35	1
TG	ENST00000518505.1			upstream_gene_variant		4
TG	ENST00000518097.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91854 AN: 151938 Hom.: 28408 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.593

GnomAD3 exomes AF: 0.582 AC: 146257 AN: 251450 Hom.: 43426 AF XY: 0.582 AC XY: 79143 AN XY: 135908

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.762

Gnomad SAS exome AF: 0.645

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.522

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.537 AC: 784336 AN: 1461824 Hom.: 213884 Cov.: 59 AF XY: 0.540 AC XY: 392555 AN XY: 727216

Gnomad4 AFR exome AF: 0.722

Gnomad4 AMR exome AF: 0.562

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.759

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.605 AC: 91943 AN: 152056 Hom.: 28447 Cov.: 33 AF XY: 0.612 AC XY: 45473 AN XY: 74324

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.659

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.586

Alfa AF: 0.546 Hom.: 56573

Bravo AF: 0.609

TwinsUK AF: 0.507 AC: 1879

ALSPAC AF: 0.518 AC: 1998

ESP6500AA AF: 0.727 AC: 3205

ESP6500EA AF: 0.518 AC: 4451

ExAC AF: 0.584 AC: 70901

Asia WGS AF: 0.681 AC: 2368 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.535

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Iodotyrosyl coupling defect Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -

Autoimmune thyroid disease, susceptibility to, 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.0040
Dann	Benign	0.25
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.070
ClinPred		0.0013	T
GERP RS		-0.44
Varity_R		0.067
gMVP		0.31

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: rs853326; hg19: chr8-133909974; COSMIC: COSV55088277; COSMIC: COSV55088277;