chr17-42329642-C-T

Variant names:

• chr17-42329642-C-T
• rs113994136
• NM_139276.3:c.1145G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_139276.3(STAT3):​c.1145G>A​(p.Arg382Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R382L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.91
• Publications: 40 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_139276.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42329642-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18307.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 17-42329642-C-T is Pathogenic according to our data. Variant chr17-42329642-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 18305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.1145G>A	p.Arg382Gln	missense_variant	Exon 13 of 24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.1145G>A	p.Arg382Gln	missense_variant	Exon 13 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:5 Other:1

Oct 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STAT3 c.1145G>A (p.Arg382Gln) results in a conservative amino acid change located in the STAT transcription factor, DNA-binding (IPR013801) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes. c.1145G>A has been reported in the literature in multiple individuals affected with Hyper IgE Syndrome (e.g. Holland 2007). It has been observed as de novo and also seen to segregate with disease. These data indicate that the variant is very likely to be associated with disease. Additionally, other variants affected the same codon have been associated with Hyper-IgE syndrome in HGMD and ClinVar (e.g. R382G, R382P and R382W). At least one publication reports experimental evidence evaluating an impact on protein function by severely reducing the DNA binding ability of the homodimer (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 17881745, 20159255, 22581330).Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 18, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Nov 12, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17676033). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.79 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018305 /PMID: 17676033). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 17676033, 17881745). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17881745). Different missense changes at the same codon (p.Arg382Gly, p.Arg382Leu, p.Arg382Pro, p.Arg382Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018304, VCV000018307, VCV002099076 /PMID: 17676033, 17881745, 20093388, 32944025 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 19, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed to be de novo in individuals affected with hyper-IgE syndrome (Holland SM, 2007). It also segregates with hyper-IgE syndrome in a family and has been identified in several individuals affected with hyper-IgE syndrome (Minegishi Y, 2007) and an individual with selective IgG subclass deficiency (Ohnishi H, 2016). This variant has been reported to affect STAT3 protein function (Minegishi Y, 2007). This sequence change replaces arginine with glutamine at codon 382 of the STAT3 protein (p.Arg382Gln). Other variant(s) that disrupt p.Arg382 residue have been determined to be pathogenic (Renner ED, 2007). The variant has been reported to the ClinVar database as Pathogenic. The p.Arg382Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Arg382Gln in STAT3 is predicted as conserved by GERP++ and PhyloP across 100 vertebratesFor these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Nov 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate markedly enhanced STAT3 AGG-element binding, increased AGG-promoter activation activity, impaired Th17 response, and reduced IgG levels resulting in increased susceptibility to recurrent infections (Minegishi et al., 2007; Xu et al., 2015; Moffitt et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18591410, 27474157, 29368105, 29402895, 20859667, 21288777, 21792878, 22500887, 22581330, 23830147, 20093388, 26384563, 25686613, 26280891, 17676033, 24452316, 17881745, 27302695, 28197791, 30410549, 31596517, 32912316, 32499645, 32581362, 33225392, 32888943, 33717144, 18602572, 29463618) -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STAT3: PM1, PM2, PS3:Moderate, PS4:Moderate, PP2, PP3, PP4 -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Pathogenic:1

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 382 of the STAT3 protein (p.Arg382Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyper-IgE syndrome (PMID: 17676033, 17881745, 20301786, 24452316, 27302695). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18305). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STAT3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 17676033, 26384563). This variant disrupts the p.Arg382 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17676033, 17881745, 17942886, 22581330). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inherited Immunodeficiency Diseases Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	M;M;.;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;.;D;.;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.020	D;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.94
MutPred		0.97		Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);.;Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);
MVP		0.98
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.69
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113994136; hg19: chr17-40481660;