rs2069561

chr8-132963038-G-A

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.5512G>A(p.Asp1838Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,613,286 control chromosomes in the GnomAD database, including 210,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1838D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (14939 hom., cov: 32)
  • Exomes 𝑓: 0.51 (195871 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.551

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=1.5006859E-5).
• BP6: Variant 8-132963038-G-A is Benign according to our data. Variant chr8-132963038-G-A is described in ClinVar as [Benign]. Clinvar id is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132963038-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.5512G>A	p.Asp1838Asn	missense_variant	29/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.5512G>A	p.Asp1838Asn	missense_variant	29/48	1	NM_003235.5	P1
TG	ENST00000518058.1	c.46G>A	p.Asp16Asn	missense_variant	1/2	1
TG	ENST00000523756.5	c.*1725G>A		3_prime_UTR_variant, NMD_transcript_variant	16/35	1
TG	ENST00000519178.5	c.880G>A	p.Asp294Asn	missense_variant	8/27	2

Frequencies

GnomAD3 genomes AF: 0.402 AC: 60999 AN: 151890 Hom.: 14938 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.429

GnomAD3 exomes AF: 0.495 AC: 124497 AN: 251260 Hom.: 32989 AF XY: 0.499 AC XY: 67688 AN XY: 135776

Gnomad AFR exome AF: 0.0938

Gnomad AMR exome AF: 0.632

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.505

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.508

GnomAD4 exome AF: 0.511 AC: 747173 AN: 1461278 Hom.: 195871 Cov.: 52 AF XY: 0.511 AC XY: 371710 AN XY: 726978

Gnomad4 AFR exome AF: 0.0898

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.489

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.507

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.525

Gnomad4 OTH exome AF: 0.480

GnomAD4 genome AF: 0.401 AC: 60995 AN: 152008 Hom.: 14939 Cov.: 32 AF XY: 0.406 AC XY: 30180 AN XY: 74296

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.516

Gnomad4 OTH AF: 0.422

Alfa AF: 0.492 Hom.: 45859

Bravo AF: 0.385

TwinsUK AF: 0.535 AC: 1984

ALSPAC AF: 0.538 AC: 2073

ESP6500AA AF: 0.120 AC: 530

ESP6500EA AF: 0.511 AC: 4398

ExAC AF: 0.484 AC: 58829

Asia WGS AF: 0.413 AC: 1438 AN: 3478

EpiCase AF: 0.510

EpiControl AF: 0.501

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

Iodotyrosyl coupling defect Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.2
Dann	Benign	0.94
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.000015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.089
Sift	Benign	0.050	D
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.026
MPC		0.068
ClinPred		0.011	T
GERP RS		1.7
Varity_R		0.067
gMVP		0.18

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: rs2069561; hg19: chr8-133975283; COSMIC: COSV55069918; COSMIC: COSV55069918;