Genetic Variant TG:p.Arg1530Gly (chr8-132923397-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003235.5(TG):c.4588C>G(p.Arg1530Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1530Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

TG
NM_003235.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

Publications

12 publications found

Variant links:

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

TG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31259137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.4588C>G	p.Arg1530Gly	missense_variant	Exon 22 of 48	ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TG	ENST00000220616.9 link	c.4588C>G	p.Arg1530Gly	missense_variant	Exon 22 of 48	1	NM_003235.5	ENSP00000220616.4	P01266-1
TG	ENST00000523756.5 link	n.*801C>G		non_coding_transcript_exon_variant	Exon 9 of 35	1		ENSP00000428628.1	H0YB42
TG	ENST00000523756.5 link	n.*801C>G		3_prime_UTR_variant	Exon 9 of 35	1		ENSP00000428628.1	H0YB42
TG	ENST00000519178.5 link	c.145C>G	p.Arg49Gly	missense_variant	Exon 2 of 27	2		ENSP00000430523.1	H0YBY1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251390

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

0.0031

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.73

M_CAP

Benign

0.054

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

PhyloP100

1.8

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.33

Sift

Uncertain

0.013

Sift4G

Uncertain

0.049

Polyphen

0.68

Vest4

0.38

MutPred

0.18

Loss of MoRF binding (P = 0.0372);

MVP

0.92

MPC

0.12

ClinPred

0.50

GERP RS

3.4

Varity_R

0.24

gMVP

0.49

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over