rs17593222

Variant names:

• chr17-42360972-C-G
• rs17593222
• NM_139276.3:c.-23-12433G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-42360972-C-G
• chr17-42360972-C-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.-23-12433G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 152,118 control chromosomes in the GnomAD database, including 347 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 0.061 (347 hom., cov: 31)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412
• Publications: 17 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0727 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	NM_139276.3	MANE Select	c.-23-12433G>C		intron	N/A	NP_644805.1
	STAT3	NM_001369512.1		c.-1-12455G>C		intron	N/A	NP_001356441.1
	STAT3	NM_001369513.1		c.-4-12452G>C		intron	N/A	NP_001356442.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	ENST00000264657.10	TSL:1 MANE Select	c.-23-12433G>C		intron	N/A	ENSP00000264657.4
	STAT3	ENST00000588969.5	TSL:1	c.-1-12455G>C		intron	N/A	ENSP00000467985.1
	STAT3	ENST00000404395.3	TSL:1	c.-1-12455G>C		intron	N/A	ENSP00000384943.3

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9226 AN: 152000 Hom.: 340 Cov.: 31

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.0518

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

GnomAD4 genome AF: 0.0609 AC: 9262 AN: 152118 Hom.: 347 Cov.: 31 AF XY: 0.0613 AC XY: 4557 AN XY: 74364

African (AFR) AF: 0.0371 AC: 1541 AN: 41486

American (AMR) AF: 0.0476 AC: 727 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3464

East Asian (EAS) AF: 0.0175 AC: 91 AN: 5186

South Asian (SAS) AF: 0.0731 AC: 352 AN: 4818

European-Finnish (FIN) AF: 0.102 AC: 1080 AN: 10586

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0744 AC: 5056 AN: 67988

Other (OTH) AF: 0.0588 AC: 124 AN: 2108

Alfa AF: 0.0358 Hom.: 21

Bravo AF: 0.0536

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.89
DANN	Benign	0.53
PhyloP100		-0.41
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: rs17593222; hg19: chr17-40512990;