chr8-133050021-A-G

Variant names:

• chr8-133050021-A-G
• rs2687836
• NM_003235.5:c.7239+19998A>G

Variant summary

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

The NM_003235.5(TG):​c.7239+19998A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,396,346 control chromosomes in the GnomAD database, including 27,678 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 0.16 (2828 hom., cov: 33)
  • Exomes 𝑓: 0.17 (24850 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.50
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7239+19998A>G		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4
SLA	NM_001045556.3	c.162-33T>C		intron_variant	Intron 4 of 8	ENST00000338087.10	NP_001039021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7239+19998A>G		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4
SLA	ENST00000338087.10	c.162-33T>C		intron_variant	Intron 4 of 8	1	NM_001045556.3	ENSP00000337548.5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24684 AN: 152144 Hom.: 2821 Cov.: 33

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.226 AC: 56791 AN: 250892 AF XY: 0.224

Gnomad AFR exome AF: 0.0876

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.172 AC: 214218 AN: 1244084 Hom.: 24850 Cov.: 18 AF XY: 0.176 AC XY: 111028 AN XY: 630572

African (AFR) AF: 0.0901 AC: 2626 AN: 29136

American (AMR) AF: 0.380 AC: 16900 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3932 AN: 24824

East Asian (EAS) AF: 0.554 AC: 21506 AN: 38814

South Asian (SAS) AF: 0.338 AC: 27818 AN: 82314

European-Finnish (FIN) AF: 0.182 AC: 9675 AN: 53288

Middle Eastern (MID) AF: 0.138 AC: 741 AN: 5364

European-Non Finnish (NFE) AF: 0.133 AC: 121319 AN: 912596

Other (OTH) AF: 0.182 AC: 9701 AN: 53306

GnomAD4 genome AF: 0.162 AC: 24695 AN: 152262 Hom.: 2828 Cov.: 33 AF XY: 0.173 AC XY: 12888 AN XY: 74440

African (AFR) AF: 0.0908 AC: 3772 AN: 41558

American (AMR) AF: 0.297 AC: 4546 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3470

East Asian (EAS) AF: 0.521 AC: 2690 AN: 5164

South Asian (SAS) AF: 0.351 AC: 1692 AN: 4818

European-Finnish (FIN) AF: 0.188 AC: 1994 AN: 10608

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8861 AN: 68028

Other (OTH) AF: 0.180 AC: 381 AN: 2112

Alfa AF: 0.152 Hom.: 864

Bravo AF: 0.167

Asia WGS AF: 0.431 AC: 1496 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0040
DANN	Benign	0.37
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2687836; hg19: chr8-134062266; COSMIC: COSV55077245; COSMIC: COSV55077245;