8-133029867-G-T

Variant names:

• chr8-133029867-G-T
• rs116723711
• NM_003235.5:c.7083G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_003235.5(TG):​c.7083G>T​(p.Ala2361Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,614,216 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2361A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (16 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.932
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.15).
• BP6: Variant 8-133029867-G-T is Benign according to our data. Variant chr8-133029867-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436999.
• BP7: Synonymous conserved (PhyloP=-0.932 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 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.7083G>T	p.Ala2361Ala	synonymous	Exon 41 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.7083G>T	p.Ala2361Ala	synonymous	Exon 41 of 48	ENSP00000220616.4
	TG	ENST00000523756.5	TSL:1	n.*3296G>T		non_coding_transcript_exon	Exon 28 of 35	ENSP00000428628.1
	TG	ENST00000523756.5	TSL:1	n.*3296G>T		3_prime_UTR	Exon 28 of 35	ENSP00000428628.1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152238 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00323 AC: 809 AN: 250508 AF XY: 0.00361

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00349 AC: 5096 AN: 1461860 Hom.: 16 Cov.: 32 AF XY: 0.00362 AC XY: 2630 AN XY: 727232

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00266 AC: 119 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26136

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

South Asian (SAS) AF: 0.00402 AC: 347 AN: 86258

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53420

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.00364 AC: 4044 AN: 1111984

Other (OTH) AF: 0.00364 AC: 220 AN: 60392

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152356 Hom.: 2 Cov.: 33 AF XY: 0.00282 AC XY: 210 AN XY: 74506

African (AFR) AF: 0.000505 AC: 21 AN: 41582

American (AMR) AF: 0.00490 AC: 75 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00384 AC: 261 AN: 68036

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00320 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Iodotyrosyl coupling defect (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.59
DANN	Benign	0.73
PhyloP100		-0.93
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: rs116723711; hg19: chr8-134042112; COSMIC: COSV105874735;