rs2069561

Variant names:

• chr8-132963038-G-A
• rs2069561
• NM_003235.5:c.5512G>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.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. 15/21 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:8
• Conservation: PhyloP100: 0.551
• Publications: 38 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]

TG Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 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.5512G>A	p.Asp1838Asn	missense	Exon 29 of 48	NP_003226.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.5512G>A	p.Asp1838Asn	missense	Exon 29 of 48	ENSP00000220616.4	P01266-1
	TG	ENST00000518058.1	TSL:1	c.43G>A	p.Asp15Asn	missense	Exon 1 of 2	ENSP00000429164.1	H0YBC5
	TG	ENST00000523756.5	TSL:1	n.*1725G>A		non_coding_transcript_exon	Exon 16 of 35	ENSP00000428628.1	H0YB42

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

GnomAD2 exomes AF: 0.495 AC: 124497 AN: 251260 AF XY: 0.499

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 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

African (AFR) AF: 0.0898 AC: 3007 AN: 33470

American (AMR) AF: 0.617 AC: 27586 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 12780 AN: 26124

East Asian (EAS) AF: 0.365 AC: 14484 AN: 39694

South Asian (SAS) AF: 0.507 AC: 43730 AN: 86240

European-Finnish (FIN) AF: 0.577 AC: 30827 AN: 53406

Middle Eastern (MID) AF: 0.446 AC: 2572 AN: 5764

European-Non Finnish (NFE) AF: 0.525 AC: 583201 AN: 1111492

Other (OTH) AF: 0.480 AC: 28986 AN: 60370

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

African (AFR) AF: 0.108 AC: 4486 AN: 41508

American (AMR) AF: 0.525 AC: 8001 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1674 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1800 AN: 5162

South Asian (SAS) AF: 0.485 AC: 2332 AN: 4812

European-Finnish (FIN) AF: 0.583 AC: 6157 AN: 10556

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.516 AC: 35085 AN: 67936

Other (OTH) AF: 0.422 AC: 890 AN: 2108

Alfa AF: 0.475 Hom.: 67762

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

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
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
PhyloP100		0.55
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
PromoterAI		-0.017	Neutral
Varity_R		0.067
gMVP		0.18
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: rs2069561; hg19: chr8-133975283; COSMIC: COSV55069918; COSMIC: COSV55069918;