8-133094892-T-G

Variant names:

• chr8-133094892-T-G
• rs2256476
• NM_003235.5:c.7240-152T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(TG):​c.7240-152T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 989,948 control chromosomes in the GnomAD database, including 256,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41545 hom., cov: 32)
  • Exomes 𝑓: 0.71 (214869 hom.)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-133094892-T-G is Benign according to our data. Variant chr8-133094892-T-G is described in ClinVar as Benign. ClinVar VariationId is 1248250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7240-152T>G		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4
SLA	NM_001045556.3	c.-319+7661A>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.7240-152T>G		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4
SLA	ENST00000338087.10	c.-319+7661A>C		intron_variant	Intron 1 of 8	1	NM_001045556.3	ENSP00000337548.5

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111610 AN: 151976 Hom.: 41503 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.738

GnomAD4 exome AF: 0.710 AC: 595053 AN: 837854 Hom.: 214869 Cov.: 11 AF XY: 0.708 AC XY: 310586 AN XY: 438934

African (AFR) AF: 0.816 AC: 17414 AN: 21328

American (AMR) AF: 0.581 AC: 23736 AN: 40850

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 17396 AN: 21846

East Asian (EAS) AF: 0.383 AC: 13828 AN: 36142

South Asian (SAS) AF: 0.612 AC: 43979 AN: 71804

European-Finnish (FIN) AF: 0.703 AC: 30125 AN: 42846

Middle Eastern (MID) AF: 0.757 AC: 2252 AN: 2976

European-Non Finnish (NFE) AF: 0.745 AC: 417466 AN: 560220

Other (OTH) AF: 0.724 AC: 28857 AN: 39842

GnomAD4 genome AF: 0.734 AC: 111698 AN: 152094 Hom.: 41545 Cov.: 32 AF XY: 0.727 AC XY: 54034 AN XY: 74336

African (AFR) AF: 0.810 AC: 33601 AN: 41488

American (AMR) AF: 0.648 AC: 9900 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2750 AN: 3468

East Asian (EAS) AF: 0.426 AC: 2198 AN: 5164

South Asian (SAS) AF: 0.602 AC: 2906 AN: 4824

European-Finnish (FIN) AF: 0.703 AC: 7426 AN: 10570

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50517 AN: 67982

Other (OTH) AF: 0.732 AC: 1544 AN: 2110

Alfa AF: 0.713 Hom.: 5401

Bravo AF: 0.730

Asia WGS AF: 0.516 AC: 1799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.8
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: rs2256476; hg19: chr8-134107136;