rs3739266

Variant names:

• chr8-133038433-A-G
• rs3739266
• NM_001045556.3:c.*91T>C

Variant summary

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

The NM_001045556.3(SLA):​c.*91T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 973,326 control chromosomes in the GnomAD database, including 116,474 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 0.50 (19528 hom., cov: 32)
  • Exomes 𝑓: 0.48 (96946 hom.)
• Consequence: SLA NM_001045556.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.444
• Publications: 6 publications found

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]

TG Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLA	NM_001045556.3	c.*91T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000338087.10	NP_001039021.1
TG	NM_003235.5	c.7239+8410A>G		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLA	ENST00000338087.10	c.*91T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001045556.3	ENSP00000337548.5
TG	ENST00000220616.9	c.7239+8410A>G		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75827 AN: 151934 Hom.: 19509 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.508

GnomAD4 exome AF: 0.477 AC: 391604 AN: 821276 Hom.: 96946 Cov.: 11 AF XY: 0.474 AC XY: 203884 AN XY: 430050

African (AFR) AF: 0.574 AC: 11766 AN: 20496

American (AMR) AF: 0.317 AC: 12391 AN: 39092

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 11058 AN: 19706

East Asian (EAS) AF: 0.208 AC: 7634 AN: 36774

South Asian (SAS) AF: 0.354 AC: 23710 AN: 66930

European-Finnish (FIN) AF: 0.491 AC: 24787 AN: 50478

Middle Eastern (MID) AF: 0.552 AC: 2376 AN: 4302

European-Non Finnish (NFE) AF: 0.512 AC: 279016 AN: 544436

Other (OTH) AF: 0.483 AC: 18866 AN: 39062

GnomAD4 genome AF: 0.499 AC: 75871 AN: 152050 Hom.: 19528 Cov.: 32 AF XY: 0.492 AC XY: 36562 AN XY: 74312

African (AFR) AF: 0.570 AC: 23620 AN: 41440

American (AMR) AF: 0.396 AC: 6058 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1943 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1037 AN: 5162

South Asian (SAS) AF: 0.331 AC: 1597 AN: 4824

European-Finnish (FIN) AF: 0.490 AC: 5186 AN: 10574

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34661 AN: 67984

Other (OTH) AF: 0.501 AC: 1056 AN: 2108

Alfa AF: 0.511 Hom.: 26041

Bravo AF: 0.498

Asia WGS AF: 0.297 AC: 1035 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.16
DANN	Benign	0.56
PhyloP100		-0.44
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: rs3739266; hg19: chr8-134050678; COSMIC: COSV55069926;