rs9909659

Variant names:

• chr17-42321817-G-A
• rs9909659
• NM_139276.3:c.2101+465C>T

Variant summary

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

The NM_139276.3(STAT3):​c.2101+465C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 151,916 control chromosomes in the GnomAD database, including 5,572 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 (5572 hom., cov: 31)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 12 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139276.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	NM_139276.3	MANE Select	c.2101+465C>T		intron	N/A	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.2101+465C>T		intron	N/A	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.2101+465C>T		intron	N/A	NP_001356442.1	P40763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	ENST00000264657.10	TSL:1 MANE Select	c.2101+465C>T		intron	N/A	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.2101+465C>T		intron	N/A	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.2098+468C>T		intron	N/A	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38290 AN: 151796 Hom.: 5562 Cov.: 31

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.252 AC: 38335 AN: 151916 Hom.: 5572 Cov.: 31 AF XY: 0.253 AC XY: 18804 AN XY: 74276

African (AFR) AF: 0.387 AC: 15997 AN: 41386

American (AMR) AF: 0.152 AC: 2312 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3464

East Asian (EAS) AF: 0.362 AC: 1869 AN: 5170

South Asian (SAS) AF: 0.310 AC: 1493 AN: 4814

European-Finnish (FIN) AF: 0.195 AC: 2063 AN: 10564

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

European-Non Finnish (NFE) AF: 0.188 AC: 12749 AN: 67952

Other (OTH) AF: 0.263 AC: 553 AN: 2106

Alfa AF: 0.229 Hom.: 1634

Bravo AF: 0.254

Asia WGS AF: 0.388 AC: 1343 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.2
DANN	Benign	0.26
PhyloP100		-0.54
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: rs9909659; hg19: chr17-40473835;