8-133083672-A-G

Variant names:

• chr8-133083672-A-G
• rs2739169
• NM_003235.5:c.7240-11372A>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.7240-11372A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 152,124 control chromosomes in the GnomAD database, including 45,168 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 0.76 (45168 hom., cov: 32)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7240-11372A>G		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4
SLA	NM_001045556.3	c.-318-8542T>C		intron_variant	Intron 1 of 8	ENST00000338087.10	NP_001039021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7240-11372A>G		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4
SLA	ENST00000338087.10	c.-318-8542T>C		intron_variant	Intron 1 of 8	1	NM_001045556.3	ENSP00000337548.5

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115990 AN: 152006 Hom.: 45117 Cov.: 32

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.763 AC: 116087 AN: 152124 Hom.: 45168 Cov.: 32 AF XY: 0.757 AC XY: 56299 AN XY: 74346

African (AFR) AF: 0.892 AC: 37037 AN: 41512

American (AMR) AF: 0.641 AC: 9792 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2582 AN: 3472

East Asian (EAS) AF: 0.450 AC: 2330 AN: 5180

South Asian (SAS) AF: 0.645 AC: 3104 AN: 4810

European-Finnish (FIN) AF: 0.749 AC: 7905 AN: 10558

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50922 AN: 67986

Other (OTH) AF: 0.732 AC: 1548 AN: 2114

Alfa AF: 0.717 Hom.: 2846

Bravo AF: 0.757

Asia WGS AF: 0.549 AC: 1912 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.065
DANN	Benign	0.42
PhyloP100		-2.7
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: rs2739169; hg19: chr8-134095916;