rs116062097

Variant names:

• chr8-132886939-T-C
• rs116062097
• NM_003235.5:c.1567T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003235.5(TG):​c.1567T>C​(p.Ser523Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,156 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.60
• Publications: 9 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=0.0060213506).
• BP6: Variant 8-132886939-T-C is Benign according to our data. Variant chr8-132886939-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 361915.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00186 (2720/1461880) while in subpopulation MID AF = 0.00867 (50/5768). AF 95% confidence interval is 0.00675. There are 6 homozygotes in GnomAdExome4. There are 1358 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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.1567T>C	p.Ser523Pro	missense	Exon 9 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.1567T>C	p.Ser523Pro	missense	Exon 9 of 48	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00160 AC: 403 AN: 251162 AF XY: 0.00169

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1461880 Hom.: 6 Cov.: 32 AF XY: 0.00187 AC XY: 1358 AN XY: 727240

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000800 AC: 69 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53408

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00210 AC: 2336 AN: 1112012

Other (OTH) AF: 0.00207 AC: 125 AN: 60394

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74454

African (AFR) AF: 0.000313 AC: 13 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00240 Hom.: 1

Bravo AF: 0.00148

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00409

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Benign	0.25	T
Sift4G	Benign	0.067	T
Polyphen		0.049	B
Vest4		0.15
MVP		0.72
MPC		0.094
ClinPred		0.0086	T
GERP RS		2.5
Varity_R		0.15
gMVP		0.35
Mutation Taster		=100/0	polymorphism

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: rs116062097; hg19: chr8-133899184;