rs853326

Variant names:

• chr8-132897729-A-G
• rs853326
• NM_003235.5:c.3082A>G

Variant summary

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

The ENST00000220616.9(TG):​c.3082A>G​(p.Met1028Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,880 control chromosomes in the GnomAD database, including 242,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (28447 hom., cov: 33)
  • Exomes 𝑓: 0.54 (213884 hom.)
• Consequence: TG ENST00000220616.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.416
• Publications: 47 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: 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=2.1309193E-6).
• BP6: Variant 8-132897729-A-G is Benign according to our data. Variant chr8-132897729-A-G is described in ClinVar as Benign. ClinVar VariationId is 12698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000220616.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.3082A>G	p.Met1028Val	missense	Exon 12 of 48	NP_003226.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.3082A>G	p.Met1028Val	missense	Exon 12 of 48	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.40A>G		non_coding_transcript_exon	Exon 1 of 35	ENSP00000428628.1
	TG	ENST00000518505.1	TSL:4	c.-21A>G		upstream_gene	N/A	ENSP00000429605.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91854 AN: 151938 Hom.: 28408 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.582 AC: 146257 AN: 251450 AF XY: 0.582

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.762

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.522

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.537 AC: 784336 AN: 1461824 Hom.: 213884 Cov.: 59 AF XY: 0.540 AC XY: 392555 AN XY: 727216

African (AFR) AF: 0.722 AC: 24178 AN: 33480

American (AMR) AF: 0.562 AC: 25127 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 15972 AN: 26136

East Asian (EAS) AF: 0.759 AC: 30134 AN: 39700

South Asian (SAS) AF: 0.648 AC: 55929 AN: 86258

European-Finnish (FIN) AF: 0.579 AC: 30933 AN: 53414

Middle Eastern (MID) AF: 0.606 AC: 3495 AN: 5768

European-Non Finnish (NFE) AF: 0.508 AC: 564743 AN: 1111952

Other (OTH) AF: 0.560 AC: 33825 AN: 60392

GnomAD4 genome AF: 0.605 AC: 91943 AN: 152056 Hom.: 28447 Cov.: 33 AF XY: 0.612 AC XY: 45473 AN XY: 74324

African (AFR) AF: 0.719 AC: 29807 AN: 41472

American (AMR) AF: 0.597 AC: 9135 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2143 AN: 3468

East Asian (EAS) AF: 0.764 AC: 3934 AN: 5152

South Asian (SAS) AF: 0.659 AC: 3180 AN: 4828

European-Finnish (FIN) AF: 0.599 AC: 6326 AN: 10562

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35475 AN: 67954

Other (OTH) AF: 0.586 AC: 1239 AN: 2116

Alfa AF: 0.555 Hom.: 81656

Bravo AF: 0.609

TwinsUK AF: 0.507 AC: 1879

ALSPAC AF: 0.518 AC: 1998

ESP6500AA AF: 0.727 AC: 3205

ESP6500EA AF: 0.518 AC: 4451

ExAC AF: 0.584 AC: 70901

Asia WGS AF: 0.681 AC: 2368 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.535

ClinVar

ClinVar submissions as Germline

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)
-	-	-	Autoimmune thyroid disease, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0040
DANN	Benign	0.25
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.42
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.070
ClinPred		0.0013	T
GERP RS		-0.44
PromoterAI		0.017	Neutral
Varity_R		0.067
gMVP		0.31
Mutation Taster		=99/1	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: rs853326; hg19: chr8-133909974; COSMIC: COSV55088277; COSMIC: COSV55088277;