rs2069568

Variant names:

• chr8-133096209-C-T
• rs2069568
• NM_003235.5:c.7408C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-133096209-C-T
• chr8-133096209-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003235.5(TG):​c.7408C>T​(p.Leu2470Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,613,656 control chromosomes in the GnomAD database, including 171,919 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12736 hom., cov: 34)
  • Exomes 𝑓: 0.46 (159183 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.32
• Publications: 17 publications found

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]

SLA (HGNC:10902): (Src like adaptor) Predicted to enable signaling receptor binding activity. Predicted to be involved in cell differentiation; innate immune response; and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in dendritic spine and focal adhesion. Predicted to be extrinsic component of cytoplasmic side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.021).
• BP6: Variant 8-133096209-C-T is Benign according to our data. Variant chr8-133096209-C-T is described in ClinVar as Benign. ClinVar VariationId is 259000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.7408C>T	p.Leu2470Leu	synonymous	Exon 43 of 48	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.-319+6344G>A		intron	N/A	NP_001039021.1	Q13239-1
	SLA	NM_001045557.3		c.11+6344G>A		intron	N/A	NP_001039022.2	Q13239-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.7408C>T	p.Leu2470Leu	synonymous	Exon 43 of 48	ENSP00000220616.4	P01266-1
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.-319+6344G>A		intron	N/A	ENSP00000337548.5	Q13239-1
	SLA	ENST00000395352.7	TSL:1	c.11+6344G>A		intron	N/A	ENSP00000378759.3	Q13239-3

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58699 AN: 152056 Hom.: 12741 Cov.: 34

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.433 AC: 108791 AN: 251364 AF XY: 0.444

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.469

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.462 AC: 675118 AN: 1461482 Hom.: 159183 Cov.: 47 AF XY: 0.463 AC XY: 336816 AN XY: 727064

African (AFR) AF: 0.190 AC: 6364 AN: 33474

American (AMR) AF: 0.300 AC: 13413 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 12274 AN: 26136

East Asian (EAS) AF: 0.361 AC: 14322 AN: 39700

South Asian (SAS) AF: 0.457 AC: 39374 AN: 86252

European-Finnish (FIN) AF: 0.571 AC: 30469 AN: 53396

Middle Eastern (MID) AF: 0.483 AC: 2788 AN: 5768

European-Non Finnish (NFE) AF: 0.476 AC: 528940 AN: 1111658

Other (OTH) AF: 0.450 AC: 27174 AN: 60380

GnomAD4 genome AF: 0.386 AC: 58707 AN: 152174 Hom.: 12736 Cov.: 34 AF XY: 0.389 AC XY: 28953 AN XY: 74400

African (AFR) AF: 0.196 AC: 8129 AN: 41520

American (AMR) AF: 0.323 AC: 4943 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1554 AN: 3472

East Asian (EAS) AF: 0.400 AC: 2073 AN: 5182

South Asian (SAS) AF: 0.456 AC: 2201 AN: 4826

European-Finnish (FIN) AF: 0.575 AC: 6079 AN: 10580

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32312 AN: 67976

Other (OTH) AF: 0.395 AC: 836 AN: 2116

Alfa AF: 0.421 Hom.: 10363

Bravo AF: 0.359

Asia WGS AF: 0.353 AC: 1230 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.467

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Iodotyrosyl coupling defect (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.8
DANN	Benign	0.75
PhyloP100		1.3
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2069568; hg19: chr8-134108453; COSMIC: COSV55065146;