chr8-133048815-G-C

Variant names:

• chr8-133048815-G-C
• rs2253035
• NM_003235.5:c.7239+18792G>C

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+18792G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 169,634 control chromosomes in the GnomAD database, including 5,540 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 0.25 (4844 hom., cov: 32)
  • Exomes 𝑓: 0.26 (696 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.605
• 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]

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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.7239+18792G>C		intron	N/A	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.249-882C>G		intron	N/A	NP_001039021.1
	SLA	NM_006748.4		c.369-882C>G		intron	N/A	NP_006739.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.7239+18792G>C		intron	N/A	ENSP00000220616.4
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.249-882C>G		intron	N/A	ENSP00000337548.5
	SLA	ENST00000427060.6	TSL:1	c.369-882C>G		intron	N/A	ENSP00000394049.2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37356 AN: 152026 Hom.: 4849 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.258 AC: 4520 AN: 17490 Hom.: 696 Cov.: 0 AF XY: 0.253 AC XY: 2374 AN XY: 9376

African (AFR) AF: 0.183 AC: 100 AN: 546

American (AMR) AF: 0.202 AC: 374 AN: 1852

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 100 AN: 388

East Asian (EAS) AF: 0.197 AC: 186 AN: 946

South Asian (SAS) AF: 0.250 AC: 709 AN: 2838

European-Finnish (FIN) AF: 0.237 AC: 160 AN: 674

Middle Eastern (MID) AF: 0.185 AC: 10 AN: 54

European-Non Finnish (NFE) AF: 0.284 AC: 2677 AN: 9428

Other (OTH) AF: 0.267 AC: 204 AN: 764

GnomAD4 genome AF: 0.246 AC: 37365 AN: 152144 Hom.: 4844 Cov.: 32 AF XY: 0.241 AC XY: 17888 AN XY: 74348

African (AFR) AF: 0.184 AC: 7653 AN: 41514

American (AMR) AF: 0.199 AC: 3047 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3472

East Asian (EAS) AF: 0.223 AC: 1156 AN: 5186

South Asian (SAS) AF: 0.260 AC: 1250 AN: 4814

European-Finnish (FIN) AF: 0.270 AC: 2858 AN: 10582

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19597 AN: 67974

Other (OTH) AF: 0.250 AC: 529 AN: 2112

Alfa AF: 0.264 Hom.: 678

Bravo AF: 0.241

Asia WGS AF: 0.215 AC: 749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.42
PhyloP100		-0.60
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: rs2253035; hg19: chr8-134061060;