chr8-133048214-T-C

Variant names:

• chr8-133048214-T-C
• rs4736618
• NM_003235.5:c.7239+18191T>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+18191T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,110 control chromosomes in the GnomAD database, including 1,392 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 0.13 (1392 hom., cov: 32)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 4 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 (AMR) allele frequency at 95% confidence interval = 0.145 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+18191T>C		intron	N/A	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.249-281A>G		intron	N/A	NP_001039021.1	Q13239-1
	SLA	NM_006748.4		c.369-281A>G		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+18191T>C		intron	N/A	ENSP00000220616.4	P01266-1
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.249-281A>G		intron	N/A	ENSP00000337548.5	Q13239-1
	SLA	ENST00000427060.6	TSL:1	c.369-281A>G		intron	N/A	ENSP00000394049.2	Q13239-5

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19831 AN: 151992 Hom.: 1397 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.130 AC: 19825 AN: 152110 Hom.: 1392 Cov.: 32 AF XY: 0.127 AC XY: 9432 AN XY: 74364

African (AFR) AF: 0.144 AC: 5967 AN: 41478

American (AMR) AF: 0.150 AC: 2286 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0549 AC: 265 AN: 4828

European-Finnish (FIN) AF: 0.0733 AC: 776 AN: 10590

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9493 AN: 67976

Other (OTH) AF: 0.131 AC: 276 AN: 2112

Alfa AF: 0.137 Hom.: 2453

Bravo AF: 0.135

Asia WGS AF: 0.0340 AC: 117 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	1.3
DANN	Benign	0.50
PhyloP100		-0.39
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: rs4736618; hg19: chr8-134060459;