8-133061860-G-T

Variant names:

• chr8-133061860-G-T
• rs1124527
• NM_003235.5:c.7239+31837G>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.7239+31837G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,032 control chromosomes in the GnomAD database, including 5,680 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 0.25 (5680 hom., cov: 32)
• Consequence: TG NM_003235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.7239+31837G>T		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4
SLA	NM_001045556.3	c.-40-1660C>A		intron_variant	Intron 2 of 8	ENST00000338087.10	NP_001039021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.7239+31837G>T		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4
SLA	ENST00000338087.10	c.-40-1660C>A		intron_variant	Intron 2 of 8	1	NM_001045556.3	ENSP00000337548.5

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37899 AN: 151914 Hom.: 5669 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.249 AC: 37917 AN: 152032 Hom.: 5680 Cov.: 32 AF XY: 0.257 AC XY: 19081 AN XY: 74312

African (AFR) AF: 0.111 AC: 4586 AN: 41500

American (AMR) AF: 0.370 AC: 5648 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2864 AN: 5146

South Asian (SAS) AF: 0.421 AC: 2027 AN: 4812

European-Finnish (FIN) AF: 0.275 AC: 2900 AN: 10562

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.265 AC: 18029 AN: 67964

Other (OTH) AF: 0.284 AC: 598 AN: 2108

Alfa AF: 0.242 Hom.: 627

Bravo AF: 0.252

Asia WGS AF: 0.484 AC: 1679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.049
DANN	Benign	0.35
PhyloP100		-1.3
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: rs1124527; hg19: chr8-134074105;