rs2069569

Variant names:

• chr8-133096302-T-C
• rs2069569
• NM_003235.5:c.7501T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-133096302-T-C
• chr8-133096302-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(TG):​c.7501T>C​(p.Trp2501Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,940 control chromosomes in the GnomAD database, including 228,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2501Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (27591 hom., cov: 32)
  • Exomes 𝑓: 0.52 (200444 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.108
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3603862E-6).
• BP6: Variant 8-133096302-T-C is Benign according to our data. Variant chr8-133096302-T-C is described in ClinVar as Benign. ClinVar VariationId is 259001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 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.7501T>C	p.Trp2501Arg	missense	Exon 43 of 48	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.-319+6251A>G		intron	N/A	NP_001039021.1	Q13239-1
	SLA	NM_001045557.3		c.11+6251A>G		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.7501T>C	p.Trp2501Arg	missense	Exon 43 of 48	ENSP00000220616.4	P01266-1
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.-319+6251A>G		intron	N/A	ENSP00000337548.5	Q13239-1
	SLA	ENST00000395352.7	TSL:1	c.11+6251A>G		intron	N/A	ENSP00000378759.3	Q13239-3

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88946 AN: 151970 Hom.: 27559 Cov.: 32

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.577

GnomAD2 exomes AF: 0.496 AC: 124629 AN: 251420 AF XY: 0.492

Gnomad AFR exome AF: 0.795

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.518 AC: 757575 AN: 1461856 Hom.: 200444 Cov.: 57 AF XY: 0.515 AC XY: 374669 AN XY: 727226

African (AFR) AF: 0.799 AC: 26752 AN: 33480

American (AMR) AF: 0.443 AC: 19817 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15606 AN: 26136

East Asian (EAS) AF: 0.230 AC: 9135 AN: 39700

South Asian (SAS) AF: 0.422 AC: 36360 AN: 86256

European-Finnish (FIN) AF: 0.462 AC: 24693 AN: 53414

Middle Eastern (MID) AF: 0.538 AC: 3103 AN: 5768

European-Non Finnish (NFE) AF: 0.531 AC: 590439 AN: 1111986

Other (OTH) AF: 0.524 AC: 31670 AN: 60392

GnomAD4 genome AF: 0.585 AC: 89025 AN: 152084 Hom.: 27591 Cov.: 32 AF XY: 0.578 AC XY: 42977 AN XY: 74330

African (AFR) AF: 0.788 AC: 32718 AN: 41506

American (AMR) AF: 0.514 AC: 7858 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1223 AN: 5152

South Asian (SAS) AF: 0.416 AC: 1999 AN: 4804

European-Finnish (FIN) AF: 0.468 AC: 4943 AN: 10568

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36326 AN: 67996

Other (OTH) AF: 0.573 AC: 1208 AN: 2108

Alfa AF: 0.542 Hom.: 76640

Bravo AF: 0.591

TwinsUK AF: 0.527 AC: 1953

ALSPAC AF: 0.539 AC: 2078

ESP6500AA AF: 0.786 AC: 3462

ESP6500EA AF: 0.527 AC: 4533

ExAC AF: 0.502 AC: 60983

Asia WGS AF: 0.341 AC: 1189 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.530

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.93
DANN	Benign	0.54
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.11
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.080	N
REVEL	Uncertain	0.30
Sift	Benign	0.50	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.46		Gain of disorder (P = 0.011)
MPC		0.12
ClinPred		0.0047	T
GERP RS		2.0
Varity_R		0.19
gMVP		0.80
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: rs2069569; hg19: chr8-134108546; COSMIC: COSV55076395;