chr8-133131869-C-T

Position:

• chr8-133131869-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003235.5(TG):​c.7920C>T​(p.Tyr2640=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,812 control chromosomes in the GnomAD database, including 180,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18754 hom., cov: 32)
  • Exomes 𝑓: 0.46 (161925 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.250

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 8-133131869-C-T is Benign according to our data. Variant chr8-133131869-C-T is described in ClinVar as [Benign]. Clinvar id is 259003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133131869-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.7920C>T	p.Tyr2640=	synonymous_variant	46/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.7920C>T	p.Tyr2640=	synonymous_variant	46/48	1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73948 AN: 151878 Hom.: 18735 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.428 AC: 107635 AN: 251420 Hom.: 24558 AF XY: 0.425 AC XY: 57743 AN XY: 135876

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.458

GnomAD4 exome AF: 0.464 AC: 677945 AN: 1461816 Hom.: 161925 Cov.: 55 AF XY: 0.460 AC XY: 334335 AN XY: 727224

Gnomad4 AFR exome AF: 0.591

Gnomad4 AMR exome AF: 0.401

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.487 AC: 73999 AN: 151996 Hom.: 18754 Cov.: 32 AF XY: 0.475 AC XY: 35323 AN XY: 74306

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.451

Gnomad4 ASJ AF: 0.567

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.503

Alfa AF: 0.490 Hom.: 23598

Bravo AF: 0.497

Asia WGS AF: 0.239 AC: 830 AN: 3476

EpiCase AF: 0.489

EpiControl AF: 0.489

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.6
DANN	Benign	0.47

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: rs2294024; hg19: chr8-134144113; COSMIC: COSV55069942; COSMIC: COSV55069942;