8-132888141-T-C

Position:

• chr8-132888141-T-C

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.2334T>C​(p.Pro778Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,406 control chromosomes in the GnomAD database, including 241,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28101 hom., cov: 31)
  • Exomes 𝑓: 0.54 (213643 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -7.75

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=-1.0).
• BP6: Variant 8-132888141-T-C is Benign according to our data. Variant chr8-132888141-T-C is described in ClinVar as [Benign]. Clinvar id is 258989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132888141-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.75 with no splicing effect.
• 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	Protein	UniProt
TG	NM_003235.5	c.2334T>C	p.Pro778Pro	synonymous_variant	10/48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.2334T>C	p.Pro778Pro	synonymous_variant	10/48	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91302 AN: 151814 Hom.: 28063 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.592

GnomAD3 exomes AF: 0.581 AC: 145393 AN: 250364 Hom.: 42975 AF XY: 0.582 AC XY: 78715 AN XY: 135336

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.763

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.536 AC: 783891 AN: 1461474 Hom.: 213643 Cov.: 72 AF XY: 0.540 AC XY: 392394 AN XY: 727018

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.561

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.761

Gnomad4 SAS exome AF: 0.651

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.602 AC: 91390 AN: 151932 Hom.: 28101 Cov.: 31 AF XY: 0.609 AC XY: 45189 AN XY: 74248

Gnomad4 AFR AF: 0.708

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.617

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.661

Gnomad4 FIN AF: 0.598

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.584

Alfa AF: 0.543 Hom.: 42175

Bravo AF: 0.605

Asia WGS AF: 0.678 AC: 2359 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.535

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0030
DANN	Benign	0.37

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: rs2069550; hg19: chr8-133900386;