chr8-132886915-C-G

Variant names:

• chr8-132886915-C-G
• rs180222
• NM_003235.5:c.1543C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003235.5(TG):​c.1543C>G​(p.Gln515Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,030 control chromosomes in the GnomAD database, including 378 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.019 (353 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0870
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004487753).
• BP6: Variant 8-132886915-C-G is Benign according to our data. Variant chr8-132886915-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258988.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0518 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.1543C>G	p.Gln515Glu	missense	Exon 9 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.1543C>G	p.Gln515Glu	missense	Exon 9 of 48	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2414 AN: 152078 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0163 AC: 4098 AN: 250794 AF XY: 0.0170

Gnomad AFR exome AF: 0.00563

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0187 AC: 27403 AN: 1461836 Hom.: 353 Cov.: 32 AF XY: 0.0190 AC XY: 13795 AN XY: 727220

African (AFR) AF: 0.00618 AC: 207 AN: 33480

American (AMR) AF: 0.0130 AC: 583 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 799 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0103 AC: 891 AN: 86258

European-Finnish (FIN) AF: 0.0129 AC: 689 AN: 53392

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5766

European-Non Finnish (NFE) AF: 0.0204 AC: 22686 AN: 1111994

Other (OTH) AF: 0.0202 AC: 1217 AN: 60394

GnomAD4 genome AF: 0.0159 AC: 2415 AN: 152194 Hom.: 25 Cov.: 32 AF XY: 0.0155 AC XY: 1151 AN XY: 74400

African (AFR) AF: 0.00542 AC: 225 AN: 41528

American (AMR) AF: 0.0166 AC: 254 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00913 AC: 44 AN: 4820

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10590

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0225 AC: 1528 AN: 68008

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0222 Hom.: 18

Bravo AF: 0.0162

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0185 AC: 159

ExAC AF: 0.0163 AC: 1979

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0272

EpiControl AF: 0.0249

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Iodotyrosyl coupling defect (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.045
DANN	Benign	0.15
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.087
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.092
Sift	Benign	0.53	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.075
ClinPred		0.0023	T
GERP RS		-1.8
Varity_R		0.032
gMVP		0.14
Mutation Taster		=100/0	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: rs180222; hg19: chr8-133899160; COSMIC: COSV99061021; COSMIC: COSV99061021;