NM_003235.5:c.7240-30525C>T

Variant names:

• chr8-133064519-C-T
• rs2248346
• NM_003235.5:c.7240-30525C>T

Variant summary

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

The NM_003235.5(TG):​c.7240-30525C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 152,184 control chromosomes in the GnomAD database, including 48,824 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 0.80 (48824 hom., cov: 33)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.834 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.7240-30525C>T		intron	N/A	NP_003226.4
	SLA	NM_001045556.3	MANE Select	c.-40-4319G>A		intron	N/A	NP_001039021.1
	SLA	NM_001045557.3		c.12-4319G>A		intron	N/A	NP_001039022.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.7240-30525C>T		intron	N/A	ENSP00000220616.4
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.-40-4319G>A		intron	N/A	ENSP00000337548.5
	SLA	ENST00000395352.7	TSL:1	c.12-4319G>A		intron	N/A	ENSP00000378759.3

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121582 AN: 152066 Hom.: 48775 Cov.: 33

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.801

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

GnomAD4 genome AF: 0.800 AC: 121691 AN: 152184 Hom.: 48824 Cov.: 33 AF XY: 0.803 AC XY: 59769 AN XY: 74412

African (AFR) AF: 0.817 AC: 33902 AN: 41518

American (AMR) AF: 0.846 AC: 12949 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2709 AN: 3466

East Asian (EAS) AF: 0.789 AC: 4075 AN: 5166

South Asian (SAS) AF: 0.828 AC: 3995 AN: 4824

European-Finnish (FIN) AF: 0.764 AC: 8090 AN: 10586

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53263 AN: 68002

Other (OTH) AF: 0.804 AC: 1702 AN: 2116

Alfa AF: 0.789 Hom.: 7493

Bravo AF: 0.802

Asia WGS AF: 0.831 AC: 2891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.15
DANN	Benign	0.43
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

Other links and lift over

dbSNP: rs2248346; hg19: chr8-134076764;