rs872643

Variant names:

• chr8-133079358-G-A
• rs872643
• NM_003235.5:c.7240-15686G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003235.5(TG):​c.7240-15686G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,242 control chromosomes in the GnomAD database, including 5,323 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5323 hom., cov: 33)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 3 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]

SLA (HGNC:10902): (Src like adaptor) Predicted to enable signaling receptor binding activity. Predicted to be involved in cell differentiation; innate immune response; and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in dendritic spine and focal adhesion. Predicted to be extrinsic component of cytoplasmic side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7240-15686G>A		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4
SLA	NM_001045556.3	c.-318-4228C>T		intron_variant	Intron 1 of 8	ENST00000338087.10	NP_001039021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7240-15686G>A		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4
SLA	ENST00000338087.10	c.-318-4228C>T		intron_variant	Intron 1 of 8	1	NM_001045556.3	ENSP00000337548.5

Frequencies

GnomAD3 genomes AF: 0.256 AC: 39012 AN: 152124 Hom.: 5321 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.247

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 39043 AN: 152242 Hom.: 5323 Cov.: 33 AF XY: 0.249 AC XY: 18547 AN XY: 74450

African (AFR) AF: 0.310 AC: 12877 AN: 41516

American (AMR) AF: 0.262 AC: 4011 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3468

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5194

South Asian (SAS) AF: 0.124 AC: 597 AN: 4828

European-Finnish (FIN) AF: 0.172 AC: 1829 AN: 10612

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17938 AN: 68006

Other (OTH) AF: 0.244 AC: 515 AN: 2114

Alfa AF: 0.257 Hom.: 875

Bravo AF: 0.262

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.41
PhyloP100		-1.2
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: rs872643; hg19: chr8-134091602;