rs2256366

Variant names:

• chr8-133044857-G-A
• rs2256366
• NM_003235.5:c.7239+14834G>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.7239+14834G>A 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 878,576 control chromosomes in the GnomAD database, including 17,877 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 0.15 (2510 hom., cov: 32)
  • Exomes 𝑓: 0.17 (15367 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 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.7239+14834G>A		intron	N/A	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.484+127C>T		intron	N/A	NP_001039021.1	Q13239-1
	SLA	NM_006748.4		c.604+127C>T		intron	N/A	NP_006739.2	Q13239-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.7239+14834G>A		intron	N/A	ENSP00000220616.4	P01266-1
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.484+127C>T		intron	N/A	ENSP00000337548.5	Q13239-1
	SLA	ENST00000427060.6	TSL:1	c.604+127C>T		intron	N/A	ENSP00000394049.2	Q13239-5

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23201 AN: 152112 Hom.: 2502 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.174 AC: 126715 AN: 726346 Hom.: 15367 AF XY: 0.179 AC XY: 67408 AN XY: 376552

African (AFR) AF: 0.0745 AC: 1422 AN: 19086

American (AMR) AF: 0.355 AC: 11592 AN: 32690

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 2599 AN: 17050

East Asian (EAS) AF: 0.508 AC: 17942 AN: 35340

South Asian (SAS) AF: 0.324 AC: 19650 AN: 60636

European-Finnish (FIN) AF: 0.172 AC: 7927 AN: 46018

Middle Eastern (MID) AF: 0.149 AC: 452 AN: 3042

European-Non Finnish (NFE) AF: 0.124 AC: 59060 AN: 477084

Other (OTH) AF: 0.171 AC: 6071 AN: 35400

GnomAD4 genome AF: 0.152 AC: 23215 AN: 152230 Hom.: 2510 Cov.: 32 AF XY: 0.164 AC XY: 12190 AN XY: 74418

African (AFR) AF: 0.0759 AC: 3153 AN: 41542

American (AMR) AF: 0.293 AC: 4474 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2458 AN: 5176

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4826

European-Finnish (FIN) AF: 0.183 AC: 1942 AN: 10604

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8417 AN: 68012

Other (OTH) AF: 0.173 AC: 365 AN: 2112

Alfa AF: 0.155 Hom.: 990

Bravo AF: 0.156

Asia WGS AF: 0.405 AC: 1408 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.76
PhyloP100		-1.7
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2256366;

hg19: chr8-134057102;