8-133094892-T-G

Position:

• chr8-133094892-T-G

Variant summary

Our verdict is Benign. Variant got -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

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SLA	NM_001045556.3	c.-319+7661A>C		intron_variant		ENST00000338087.10	NP_001039021.1
TG	NM_003235.5	c.7240-152T>G		intron_variant		ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7240-152T>G		intron_variant		1	NM_003235.5	ENSP00000220616	P1
SLA	ENST00000338087.10	c.-319+7661A>C		intron_variant		1	NM_001045556.3	ENSP00000337548	P1

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

Gnomad4 AFR exome AF: 0.816

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.703

Gnomad4 NFE exome AF: 0.745

Gnomad4 OTH exome AF: 0.724

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

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.793

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.602

Gnomad4 FIN AF: 0.703

Gnomad4 NFE AF: 0.743

Gnomad4 OTH AF: 0.732

Alfa AF: 0.709 Hom.: 5137

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.8
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs2256476; hg19: chr8-134107136;