rs8074524

Variant names:

• chr17-42317580-C-T
• rs8074524
• NM_139276.3:c.2102-356G>A

Variant summary

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

The NM_139276.3(STAT3):​c.2102-356G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 373,194 control chromosomes in the GnomAD database, including 11,276 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 (5193 hom., cov: 32)
  • Exomes 𝑓: 0.22 (6083 hom.)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 28 publications found

Genes affected

STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

STAT3 Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 1, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.2102-356G>A		intron_variant	Intron 21 of 23	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.2102-356G>A		intron_variant	Intron 21 of 23	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37252 AN: 151904 Hom.: 5183 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.224 AC: 49559 AN: 221172 Hom.: 6083 Cov.: 0 AF XY: 0.232 AC XY: 27127 AN XY: 117110

African (AFR) AF: 0.369 AC: 2614 AN: 7090

American (AMR) AF: 0.137 AC: 1458 AN: 10610

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 1860 AN: 6478

East Asian (EAS) AF: 0.358 AC: 4696 AN: 13134

South Asian (SAS) AF: 0.298 AC: 9730 AN: 32608

European-Finnish (FIN) AF: 0.200 AC: 1916 AN: 9590

Middle Eastern (MID) AF: 0.254 AC: 226 AN: 890

European-Non Finnish (NFE) AF: 0.189 AC: 24246 AN: 128552

Other (OTH) AF: 0.230 AC: 2813 AN: 12220

GnomAD4 genome AF: 0.245 AC: 37295 AN: 152022 Hom.: 5193 Cov.: 32 AF XY: 0.246 AC XY: 18292 AN XY: 74332

African (AFR) AF: 0.363 AC: 15017 AN: 41410

American (AMR) AF: 0.150 AC: 2286 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3466

East Asian (EAS) AF: 0.360 AC: 1863 AN: 5172

South Asian (SAS) AF: 0.305 AC: 1469 AN: 4818

European-Finnish (FIN) AF: 0.196 AC: 2069 AN: 10578

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12753 AN: 67984

Other (OTH) AF: 0.256 AC: 539 AN: 2106

Alfa AF: 0.209 Hom.: 2413

Bravo AF: 0.246

Asia WGS AF: 0.389 AC: 1347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.67
PhyloP100		-0.21
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: rs8074524; hg19: chr17-40469598;