rs141561325

Variant names:

• chr8-132871566-G-A
• rs141561325
• NM_003235.5:c.478+15G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-132871566-G-A
• chr8-132871566-G-C
• chr8-132871566-G-T

Variant summary

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

The NM_003235.5(TG):​c.478+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,611,436 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (93 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00700
• 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: PanelApp Australia, 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 (BayesDel_noAF=-0.82).
• BP6: Variant 8-132871566-G-A is Benign according to our data. Variant chr8-132871566-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0644 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.478+15G>A		intron	N/A	NP_003226.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.478+15G>A		intron	N/A	ENSP00000220616.4	P01266-1
	TG	ENST00000523901.1	TSL:5	n.*329+15G>A		intron	N/A	ENSP00000427871.1	E5RG33

Frequencies

GnomAD3 genomes AF: 0.00770 AC: 1172 AN: 152164 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00972 AC: 2419 AN: 248864 AF XY: 0.00757

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.0621

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00218 AC: 3180 AN: 1459154 Hom.: 93 Cov.: 31 AF XY: 0.00188 AC XY: 1363 AN XY: 725328

African (AFR) AF: 0.000867 AC: 29 AN: 33456

American (AMR) AF: 0.0586 AC: 2619 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00449 AC: 178 AN: 39636

South Asian (SAS) AF: 0.00169 AC: 146 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000881 AC: 5 AN: 5676

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1109822

Other (OTH) AF: 0.00287 AC: 173 AN: 60286

GnomAD4 genome AF: 0.00766 AC: 1167 AN: 152282 Hom.: 51 Cov.: 32 AF XY: 0.00950 AC XY: 707 AN XY: 74460

African (AFR) AF: 0.00166 AC: 69 AN: 41570

American (AMR) AF: 0.0679 AC: 1038 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.000601 Hom.: 0

Bravo AF: 0.0122

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.54
PhyloP100		-0.0070
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: rs141561325; hg19: chr8-133883811;