rs2293152

Variant names:

• chr17-42329511-G-C
• rs2293152
• NM_139276.3:c.1233+43C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-42329511-G-C
• chr17-42329511-G-A
• chr17-42329511-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139276.3(STAT3):​c.1233+43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,613,902 control chromosomes in the GnomAD database, including 307,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33971 hom., cov: 32)
  • Exomes 𝑓: 0.61 (273364 hom.)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.881
• Publications: 118 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-42329511-G-C is Benign according to our data. Variant chr17-42329511-G-C is described in ClinVar as Benign. ClinVar VariationId is 1233827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 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.1233+43C>G		intron	N/A	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.1233+43C>G		intron	N/A	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.1233+43C>G		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.1233+43C>G		intron	N/A	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.1233+43C>G		intron	N/A	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.1233+43C>G		intron	N/A	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99670 AN: 151952 Hom.: 33929 Cov.: 32

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.637

GnomAD2 exomes AF: 0.588 AC: 147772 AN: 251422 AF XY: 0.593

Gnomad AFR exome AF: 0.854

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.523

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.609 AC: 889802 AN: 1461830 Hom.: 273364 Cov.: 49 AF XY: 0.608 AC XY: 442479 AN XY: 727220

African (AFR) AF: 0.856 AC: 28666 AN: 33480

American (AMR) AF: 0.439 AC: 19641 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 14601 AN: 26136

East Asian (EAS) AF: 0.582 AC: 23107 AN: 39690

South Asian (SAS) AF: 0.625 AC: 53869 AN: 86258

European-Finnish (FIN) AF: 0.585 AC: 31231 AN: 53418

Middle Eastern (MID) AF: 0.592 AC: 3415 AN: 5768

European-Non Finnish (NFE) AF: 0.610 AC: 678344 AN: 1111960

Other (OTH) AF: 0.611 AC: 36928 AN: 60396

GnomAD4 genome AF: 0.656 AC: 99769 AN: 152072 Hom.: 33971 Cov.: 32 AF XY: 0.649 AC XY: 48265 AN XY: 74358

African (AFR) AF: 0.850 AC: 35296 AN: 41512

American (AMR) AF: 0.507 AC: 7747 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1955 AN: 3470

East Asian (EAS) AF: 0.549 AC: 2837 AN: 5166

South Asian (SAS) AF: 0.629 AC: 3036 AN: 4828

European-Finnish (FIN) AF: 0.569 AC: 6003 AN: 10546

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40782 AN: 67954

Other (OTH) AF: 0.641 AC: 1351 AN: 2106

Alfa AF: 0.587 Hom.: 14676

Bravo AF: 0.659

Asia WGS AF: 0.658 AC: 2283 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant (1)
-	-	1	not specified (1)
-	-	1	STAT3-related early-onset multisystem autoimmune disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs2293152; hg19: chr17-40481529; COSMIC: COSV52884045; COSMIC: COSV52884045;